Protección miocárdica

Redox Rep. 2025 Dec;30(1):2565033. doi: 10.1080/13510002.2025.2565033. Epub 2025 Sep 29.

ABSTRACT

OBJECTIVES: Doxorubicin (DOX) induces dose-dependent cardiotoxicity, primarily through oxidative stress and metabolic dysregulation. Although NAD+ deficiency has been implicated in cardiovascular pathology, its role in DOX-induced cardiotoxicity (DIC) remains poorly understood. This study investigated NAD+ metabolism dysregulation as a redox-sensitive mechanism in DIC pathogenesis.

METHODS: Human cardiomyocytes (AC16), mouse atrial myocytes (HL-1), and C57BL/6 mice were used to establish the DIC model. The role and mechanism of NAD+ in DIC were investigated using a range of methods.

RESULTS: Using integrated in vitro and in vivo models, we demonstrated that DOX induces myocardial oxidative damage accompanied by NAD+ depletion. Exogenous NAD+ supplementation mitigated the DOX-induced cardiomyocyte death and redox imbalance. Mechanistically, pharmacological CD38 inhibition with 78C or genetic silencing failed to restore the NAD+ pool, whereas nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) overexpression, combined with nicotinamide mononucleotide (NMN) administration, effectively rescued NAD+ levels and attenuated oxidative stress. Computational and functional analyses identified FOXO1 as a transcriptional repressor of NMNAT3 following DOX exposure.

CONCLUSION: This study establishes the dysregulation of the FOXO1-NMNAT3 axis as a key mechanism underlying NAD+ depletion in DIC. Targeting this axis through NAD+ replenishment, particularly by activating NMNAT3, offers a novel redox-based therapeutic strategy against DIC.

PMID:41021886 | PMC:PMC12481541 | DOI:10.1080/13510002.2025.2565033

PLoS One. 2025 Sep 29;20(9):e0333083. doi: 10.1371/journal.pone.0333083. eCollection 2025.

ABSTRACT

This study aimed to evaluate the safety and efficacy of a modified, bloodless Del Nido (DN) cardioplegia solution in patients undergoing isolated aortic valve replacement (AVR). A total of 370 patients who underwent isolated AVR between 2015 and 2022 were retrospectively analyzed. Patients were categorized into two groups based on the cardioplegia solution used: the bloodless DN group (N = 180) and the histidine-tryptophan-ketoglutarate (HTK) group (N = 190). To reduce selection bias and adjust for baseline differences, inverse probability of treatment weighting analysis was performed. There was no significant difference in in-hospital mortality between the two groups (HTK vs. DN: 1.2% vs. 0.9%, P = 0.554). However, the rate of spontaneous sinus rhythm restoration without the need for defibrillation following aortic cross-clamp release was significantly higher in the DN group (40.0% vs. 75.2%, P < 0.001). Additionally, the initial postoperative lactate level (3.0 ± 2.6 mmol/L vs. 2.2 ± 1.4 mmol/L, P = 0.002), and the incidence of low cardiac output syndrome (9.4% vs. 1.7%, P < 0.001) were significantly lower in the DN group compared to the HTK group. Other postoperative morbidities did not differ significantly between the groups. The modified bloodless Del Nido cardioplegia demonstrated favorable myocardial protection and early clinical outcomes compared to HTK solution in patients undergoing isolated AVR. These findings suggest that the bloodless Del Nido technique may be a viable alternative, although further validation in larger, prospective studies is warranted.

PMID:41021556 | PMC:PMC12478951 | DOI:10.1371/journal.pone.0333083

Postgrad Med J. 2025 Sep 29:qgaf163. doi: 10.1093/postmj/qgaf163. Online ahead of print.

ABSTRACT

BACKGROUND: New-onset atrial fibrillation (AF) in the setting of acute myocardial infarction (AMI) is associated with higher risks of stroke and mortality. However, current guidelines lack specific antithrombotic recommendations for this population. This study aimed to explore the association between rivaroxaban and the prognosis of patients with AMI and new-onset AF.

METHODS: This retrospective cohort study included patients with AMI and new-onset AF receiving dual antiplatelet therapy between August 2016 and June 2023 in Tianjin, China. New-onset AF (transient or nontransient) was defined as the first diagnosis of AF following AMI. The primary outcome was stroke.

RESULTS: 2477 patients were identified, including 141 rivaroxaban users and 2336 patients without oral anticoagulants (OAC). Over a median follow-up of 922 days, rivaroxaban users had a 5.7% lower risk of stroke than non-OAC users, although this was not statistically significant (19.9% vs. 25.6%; P = .152). Despite the suggestion of a protective trend, multivariable Cox regression showed that rivaroxaban use was not associated with a lower risk of stroke (hazard ratio, 0.77; 95% confidence interval, 0.52-1.13, P = .187). After propensity score matching, 155 transient (rivaroxaban: 42; non-OAC: 113) and 295 nontransient AF patients (rivaroxaban: 85; non-OAC: 210) were included. No significant association was observed between rivaroxaban and stroke, ischemic stroke, hemorrhagic stroke, all-cause mortality, cardiovascular mortality, bleeding, or major bleeding.

CONCLUSION: No significant association was observed between rivaroxaban and clinical outcomes in patients with AMI and new-onset AF. Given the small sample size and limited statistical power, the findings are exploratory and require further validation. Key messages What is already known on this topic: Evidence from previous studies indicates that acute myocardial infarction (AMI) patients with new-onset atrial fibrillation (AF) are associated with higher risks of ischemic stroke and mortality. However, the association between rivaroxaban and the prognosis of patients with AMI and new-onset AF remains uncertain. What this study adds: Among patients with AMI and new-onset AF receiving dual antiplatelet therapy, no significant differences were observed between rivaroxaban users and non-oral anticoagulant users in terms of the risks of stroke, ischemic stroke, hemorrhagic stroke, all-cause mortality, cardiovascular mortality, bleeding, or major bleeding. However, these results should be interpreted with caution due to the small sample size and limited statistical power of the study. How this study might affect research, practice or policy: Future prospective large-scale studies and randomized controlled trials are needed to further examine the role of rivaroxaban and other types of oral anticoagulants in patients with AMI and new-onset AF.

PMID:41020767 | DOI:10.1093/postmj/qgaf163

Oxid Med Cell Longev. 2025 Sep 18;2025:7786043. doi: 10.1155/omcl/7786043. eCollection 2025.

ABSTRACT

Doxorubicin (Doxo) is an anthracycline widely used as a chemotherapeutic agent for many solid and hematological cancers. Its clinical use is limited due to a cumulative dose-dependent and irreversible cardiotoxicity that can cause progressive cardiomyopathy and congestive heart failure. A cardioprotective therapy that can decrease heart damage without reducing the anticancer efficacy during Doxo therapy is of utmost importance. Anthocyanins (ACNs) are renowned cardioprotective agents thanks to their antioxidant and anti-inflammatory properties. An ACN-rich diet from purple corn, which mainly contains cyanidin 3-glucoside (C3G) and its acetylated derivatives, has been previously shown to be effective in reducing Doxo-induced cardiotoxicity in mice. Aiming at unveiling the molecular mechanisms involved in ACN protection, we considered the fibroblast growth factor 21/AMP-activated protein kinase/SIRTUIN1 (FGF21/AMPK/SIRT1)/p53 pathway in murine HL-1 cardiomyocytes treated with Doxo in the presence or absence of purple corn extract (RED). Our work shows that Doxo-induced AMPK activation is restored to control levels by the RED extract. p53 acetylation was increased by the RED extract and upon Sirt1 silencing, indicating that p53 acetylation is SIRT1-dependent and suggesting that the RED extract may affect SIRT1 activity through AMPK. Notably, increased p53 acetylation led to decreased levels of cleaved-caspase 3 and Puma and p21 transcript levels, indicating a reduced level of apoptosis. The RED-induced cardioprotection and p53 acetylation were confirmed in mouse primary cardiomyocytes. In conclusion, the RED extract may prevent cardiomyocytes apoptosis through the modulation of AMPK and acetylation of p53.

PMID:41018278 | PMC:PMC12463520 | DOI:10.1155/omcl/7786043

Ther Adv Med Oncol. 2025 Sep 23;17:17588359251378245. doi: 10.1177/17588359251378245. eCollection 2025.

ABSTRACT

BACKGROUND: Real-world evidence on protective effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) against anthracycline- or trastuzumab-induced cardiotoxicity in patients with breast cancer is limited.

OBJECTIVES: To examine the cardioprotective benefits of SGLT2i in older women with early-stage breast cancer (EBC) following anthracycline- and/or trastuzumab-based therapies.

DESIGN: This was a retrospective cohort study using the 2011-2019 SEER-Medicare database.

METHODS: We identified women aged over 65.5 years and diagnosed with stage I-III BC who received anthracycline and/or trastuzumab and subsequently initiated antidiabetic medications. Propensity scores were used to match one new-user episode of SGLT2i with four new-user episodes of other antidiabetic medications (OAMs). The primary outcome was a composite endpoint consisting of heart failure (HF), stroke, myocardial infarction, and arrhythmia. Secondary outcomes included hospitalization due to HF (HHF) and incident HF or cardiomyopathy (CM). Cause-specific hazard ratios (csHR) between SGLT2i and OAMs groups were assessed for each outcome, with all-cause death treated as a competing event.

RESULTS: From 1195 women examined, 1777 new-user episodes were identified. After 1:4 matching, there were 131 episodes in the SGLT2i group and 469 in the OAM group. Covariates were well-balanced between groups. No statistically significant differences were observed in the composite cardiovascular (csHR = 0.71; 95% confidence interval (CI): 0.44-1.15; p = 0.24), HHF (csHR = 0.92; 95% CI: 0.10-8.27; p = 0.94), or incident HF/CM (csHR = 0.77; 95% CI: 0.45-1.34; p = 0.36) outcomes. Results were consistent across individual SGLT2i and clinical subgroups, including those with/without established cardiovascular diseases and those exposed to various cardiotoxic cancer treatments.

CONCLUSION: No significant differences in cardiovascular risks were found between women with EBC who initiated SGLT2i versus OAMs after anthracycline or trastuzumab treatments, which might be due to the limited sample size. Further investigation through clinical trials is necessary to confirm the cardioprotective potential of SGLT2i among patients with EBC.

PMID:41018041 | PMC:PMC12461033 | DOI:10.1177/17588359251378245

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2025 Jul;37(7):693-697. doi: 10.3760/cma.j.cn121430-20250318-00270.

ABSTRACT

Peroxisome proliferator activated receptor-α (PPAR-α) is significantly expressed in various tissues such as the liver, kidney, myocardium, and skeletal muscle, which plays a central role in the development of various diseases by regulating key physiological processes such as energy homeostasis, redox balance, inflammatory response, and ferroptosis. As an important metabolic and excretory organ of the body, renal dysfunction can lead to water and electrolyte imbalance, toxin accumulation, and multiple system complications. The causes of kidney injury are complex and diverse, including acute injury factors (such as ischemia/reperfusion, nephrotoxic drugs, septic shock, and immune glomerulopathy), as well as chronic progressive causes [such as metabolic disease-related nephropathy, hypertensive nephropathy (HN)], and risk factors such as alcohol abuse, obesity, and aging. This review briefly describes the structure, function, and activity regulation mechanism of PPAR-α, systematically elucidates the molecular regulatory network of PPAR-α in the pathological process of kidney injury including acute kidney injury (AKI) such as renal ischemia/reperfusion injury (IRI), drug-induced AKI, sepsis-associated acute kidney injury (SA-AKI), glomerulonephritis, chronic kidney disease (CKD) such as diabetic nephropathy (DN), HN, and other kidney injury, and summarizes the mechanisms related to PPAR-α regulation of kidney injury, including regulation of metabolism, antioxidation, anti-inflammation, anti-fibrosis, and anti-ferroptosis. This review also evaluates PPAR-α's medical value as a novel therapeutic target, and aims to provide theoretical basis for the development of kidney protection strategies based on PPAR-α targeted intervention.

PMID:41017187 | DOI:10.3760/cma.j.cn121430-20250318-00270

Biomedicines. 2025 Sep 12;13(9):2254. doi: 10.3390/biomedicines13092254.

ABSTRACT

Aims: Myocardial inflammation in cardiac amyloidosis is associated with poor clinical outcomes. This study aimed to (a) investigate the relationship between peripheral blood cytokine levels and the presence of inflammatory cells within the myocardium, and to (b) evaluate the potential of cytokines as predictors of major adverse cardiovascular events (MACE) in transthyretin (ATTR) and immunoglobulin light chain (AL) cardiac amyloidosis. Methods: Peripheral blood samples were collected from 50 patients with cardiac ATTR or AL amyloidosis between 2018 and 2023 at baseline and every three months during follow-up visits. Cytokine analysis was performed using Olink's Proximity Extension Assay. For MACE prediction analysis, only patients with MACE occurring within ±14 days of a study visit were included (n = 16). Associations were evaluated using linear models. Results: No significant associations were identified between the EMB-confirmed myocardial presence of inflammatory cells and cytokine levels. There was a trend of weak-to-moderate associations between serial blood cytokine levels and MACE, albeit this was non-significant after adjustment for multiple testing (FDR): r2 = 0.28 for PON3 (p = 0.00075, FDR = 0.28), SIGLEC1 (p = 0.00077, FDR = 0.28), and IL-6 (p = 0.00086, FDR = 0.31). Conclusions: Peripheral blood cytokine levels were not reliable biomarkers for the myocardial presence of inflammatory cells. PON3, SIGLEC1, and IL-6 demonstrated a statistically non-significant trend of a weak-to-moderate association with MACE in cardiac amyloidosis. Since we recently demonstrated that amyloidosis with an inflammatory component is associated with poor outcomes, these additional findings underscore the need for alternative approaches to identify and manage inflammation in this patient population.

PMID:41007815 | PMC:PMC12467096 | DOI:10.3390/biomedicines13092254

J Neuroinflammation. 2025 Sep 26;22(1):213. doi: 10.1186/s12974-025-03538-9.

ABSTRACT

T cell dysfunction is a pivotal driving factor in autoimmune diseases, yet its underlying regulatory mechanisms remain incompletely understood. The role of long non-coding RNAs (lncRNAs) in immune regulation has gradually been recognized, although their functional mechanisms in T cells remain elusive. This study focuses on lncBADR (LncRNA Branched-chain Amino acids Degradation Regulator), elucidating its mechanism by which it regulates branched-chain amino acids (BCAAs) metabolism to influence T cell effector functions. Mice with specific knockout of lncBADR (T celllncBADR-/-) exhibited markedly ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. Mechanistic investigations revealed that lncBADR inhibits BCAAs degradation by binding to the enzymes Mccc1 and Pcca, leading to the accumulation of BCAAs within T-cells. This, in turn, activates the mTOR-Stat1 signaling pathway, promoting IFN-γ secretion and exacerbating EAE pathology. In contrast, knockout of lncBADR restored BCAAs degradation, significantly reducing IFN-γ secretion in T cells and suppressing their pathogenic functions. Further studies demonstrated that high-BCAAs feeding partially reversed the protective effects of lncBADR knockout, indicating that lncBADR plays a crucial role in autoimmune inflammation by regulating BCAAs metabolism. This study offers new insights into targeting lncBADR or modulating BCAAs metabolism as potential therapeutic strategies for autoimmune diseases.

PMID:41013574 | PMC:PMC12465721 | DOI:10.1186/s12974-025-03538-9

Nutrients. 2025 Sep 22;17(18):3025. doi: 10.3390/nu17183025.

ABSTRACT

Background: Abnormal mitochondrial energy metabolism is a key factor in the development and progression of cardiac hypertrophy. Hopeaphenol (HP), a tetramer of the natural polyphenol resveratrol, exhibits higher biological activity than resveratrol, but its specific role in cardiac hypertrophy and underlying mechanisms remains unclear. Methods: This study explored the protective effect and mechanism of hopeaphenol on cardiac hypertrophy through in vivo and in vitro experiments. In in vivo experiments, transverse aortic constriction (TAC) was used to induce cardiac hypertrophy in mice; HE, Masson, and WGA staining were applied to observe myocardial changes, ELISA was used to detect animal serum indicators, and the Cellular Thermal Shift Assay (CETSA) was conducted to verify the interaction between hopeaphenol and AMPK. In in vitro experiments, angiotensin II (Ang II) was used to induce hypertrophy of HL-1 cardiomyocytes, and the AMPK-specific inhibitor Compound C was employed to confirm the role of the AMPK pathway. Results: In in vivo experiments, TAC-induced cardiac hypertrophy in mice was characterized by left ventricular cavity enlargement and decreased ejection fraction; hopeaphenol treatment significantly improved these cardiac function indices, and HE, Masson, and WGA staining confirmed that hopeaphenol could restore cardiomyocyte morphology and reduce fibrosis. ELISA results of animal serum showed that hopeaphenol could improve metabolic disorders in TAC mice. Furthermore, CETSA confirmed a direct interaction between hopeaphenol and AMPK. In in vitro experiments, hopeaphenol reduced Ang II-induced hypertrophy and apoptosis of HL-1 cardiomyocytes, enhanced mitochondrial membrane potential, and decreased reactive oxygen species (ROS) levels by activating the AMPK pathway; moreover, the AMPK-specific inhibitor Compound C blocked these effects. This suggests that hopeaphenol's cardioprotective effect is largely mediated by AMPK activation. Conclusions: The protective effect of hopeaphenol on cardiac hypertrophy is highly dependent on the activation of the AMPK signaling pathway, with CETSA and molecular docking supporting direct binding between hopeaphenol and AMPK; this pathway improves mitochondrial dysfunction through AMPK, thereby alleviating heart failure caused by pressure overload. This finding identifies hopeaphenol as a potential candidate for further development in the prevention and treatment of heart failure.

PMID:41010549 | PMC:PMC12472553 | DOI:10.3390/nu17183025

Int J Mol Sci. 2025 Sep 13;26(18):8937. doi: 10.3390/ijms26188937.

ABSTRACT

Proprotein Convertase Subtilisin/Kexin type 9 PCSK9 inhibitors (PCSK9i) are a novel class of cholesterol-lowering agents that also offer protection against tissue ischemia by reducing apoptosis, pyroptosis, and myocardial infarct size. This study evaluated the effects of the PCSK9 inhibitor PEP 2-8 during hypothermic perfusion (HP) in a rat model of donation after circulatory death (DCD) kidney transplantation. DCD kidneys were perfused at 4 °C for six hours with either Perf-Gen solution alone (control) or Perf-Gen supplemented with PEP 2-8. Glucose and lactate dehydrogenase (LDH) levels were measured at baseline and after six hours (T6h). At T6h, kidneys were evaluated for ischemic injury, tubular cell proliferation, apoptosis, nitrotyrosine (N-Tyr) staining, tissue ATP and LDH levels, and gene expression of PCSK9 and NOX4. Metabolomic profiling was also performed. PEP 2-8 treatment significantly reduced PCSK9 expression, decreased tubular ischemic injury and necrosis, and lowered LDH release. Treated kidneys showed enhanced tubular cell proliferation, reduced apoptosis, and diminished oxidative stress, indicated by decreased N-Tyr staining and NOX4 expression. Energy metabolism was improved, with higher tissue ATP and glucose levels observed in the PEP 2-8 group. Metabolomic analysis further supported the antioxidant effects of PEP 2-8. This is the first study to demonstrate that PEP 2-8 administered during pre-transplant hypothermic perfusion provides renal protection by improving energy metabolism and reducing oxidative stress in the context of ischemic injury.

PMID:41009504 | PMC:PMC12469581 | DOI:10.3390/ijms26188937

Int J Mol Sci. 2025 Sep 12;26(18):8902. doi: 10.3390/ijms26188902.

ABSTRACT

The purpose of this study was to explore the protective effect of 8 weeks of Moderate Intensity Continuous Training (MICT) on TMAO-induced myocardial injury in mice and its metabolic regulatory mechanism based on nuclear magnetic resonance (NMR) metabolomics methods. Male C57BL/6J mice were randomly allocated into the following groups: Control group (Con, n = 15), TMAO-induced myocardial injury group (TMAO, n = 15), and TMAO-induced with MICT intervention group (Exe, n = 15). TMAO and Exe groups underwent 8 weeks of high-dose TMAO gavage to establish a myocardial injury model, with the Exe group additionally receiving 8 weeks of MICT intervention (60 min/session, 5 sessions/week, 50% MRC). After the 8 weeks of interventions, the mouse heart function was tested using cardiac ultrasound equipment; myocardial histology was evaluated using HE staining; and myocardial tissue samples were collected for NMR metabolomics analysis. Compared with the Con group, the HR in the TMAO group was significantly increased, while EF and LVFS were significantly decreased. Compared with the TMAO group, the HR in the Exe group was significantly reduced, and EF and LVFS were significantly increased; NMR metabolomics analysis showed that, compared with the Con group, five metabolic pathways including phenylalanine metabolism, tyrosine metabolism, and TCA cycle were significantly altered in the TMAO group; compared with the TMAO group, ten metabolic pathways related to amino acid metabolism (such as alanine, glycine, etc.), energy metabolism (TCA cycle), and oxidative stress (purine metabolism) were significantly regulated in the Exe group. MICT could effectively alleviate TMAO-induced myocardial injury in mice by regulating multiple targets within the myocardial metabolic pathways. These findings provide a theoretical basis for the clinical application of exercise intervention in myocardial injury treatment.

PMID:41009469 | PMC:PMC12470193 | DOI:10.3390/ijms26188902

Antioxidants (Basel). 2025 Sep 22;14(9):1140. doi: 10.3390/antiox14091140.

ABSTRACT

Heat stress (HS), a pervasive environmental stressor, significantly disrupts systemic physiological homeostasis, posing substantial threats to human and animal health. Sheng Mai San (SMS), a classic Traditional Chinese Medicine (TCM) formula, exerts its therapeutic effects by replenishing qi (the vital energy governing physiological functions) and nourishing yin (the material basis responsible for moistening and cooling actions). This formula demonstrates significant efficacy in astringing sweating and preventing collapse. However, its precise molecular mechanisms against HS-induced myocardial injury remain incompletely elucidated. This study initially employed physicochemical analytical methods to determine the contents of total polysaccharides, saponins, and flavonoids in SMS and evaluated its antioxidant activity. Subsequently, both in vitro and in vivo rat models of HS were established to systematically assess the alterations in reactive oxygen species (ROS), antioxidant enzymes (GSH, SOD, CAT), and heat shock proteins (HSP70, HSP90) following SMS intervention, thereby investigating HS-induced myocardial injury and the protective effects of SMS. Furthermore, Western blot, immunofluorescence, and qRT-PCR techniques were utilized to quantitatively analyze key molecules in the Keap1-Nrf2-HO-1 and Stub1-HSF1 signaling pathways. The results demonstrated that total polysaccharides were the most concentrated in SMS, followed by total saponins. This formula exhibited potent free radical scavenging capacity against DPPH, ABTS, and OH-, along with significant reducing activity. HS-induced myocardial injury reached its peak severity at 6-12 h post-stress exposure. SMS intervention effectively suppressed excessive ROS generation, enhanced the activities of antioxidant enzymes (GSH, SOD, and CAT), and downregulated HSP70 and HSP90 mRNA expression levels, thereby significantly mitigating cardiomyocyte damage. Mechanistic investigations revealed that SMS conferred cardioprotection through dual modulation of the Keap1-Nrf2-HO-1 and Stub1-HSF1 signaling pathways. This study not only provides a novel TCM-based therapeutic strategy for preventing and treating HS-related cardiovascular disorders but also establishes a crucial theoretical foundation for further exploration of SMS's pharmacological mechanisms and clinical applications.

PMID:41009044 | PMC:PMC12466528 | DOI:10.3390/antiox14091140

Antioxidants (Basel). 2025 Sep 19;14(9):1137. doi: 10.3390/antiox14091137.

ABSTRACT

NADPH oxidase 4 (NOX4) plays a crucial role in regulating cardiac function and pathology through its involvement in oxidative stress, fibrosis, and maladaptive remodeling. Studies have demonstrated that NOX4 is upregulated in response to various cardiovascular stressors, including heart failure, myocardial infarction, arrhythmias, and diabetes. This upregulation contributes to detrimental processes like fibrosis, hypertrophy, and inflammation, which are hallmarks of cardiovascular diseases. Inhibition or knockout of NOX4 has shown promise in mitigating these pathological changes, suggesting that NOX4 represents a potential therapeutic target for treating heart disease. However, NOX4's role is not entirely negative. It also plays a protective role in the heart, supporting myocardial remodeling and angiogenesis and regulating cardiac energy metabolism. Its constitutive ROS production and ability to respond to environmental cues like hypoxia help maintain cellular homeostasis and facilitate adaptive responses to stress. The impact of NOX4 on cardiac health depends not only on its expression level but also on the nature of the stress, the duration of activation, and the balance between protective signaling and oxidative injury. Collectively, the findings suggest that NOX4 functions as a redox sensor, modulating cellular responses to fluctuations in oxidative stress by signaling the need to re-establish redox homeostasis. The ultimate impact of cardiac NOX4 activity, whether protective or deleterious, is highly context-dependent and should not be evaluated through a singular interpretative framework. In conclusion, NOX4 is a dual-function enzyme that can both exacerbate and protect against cardiac pathology, making it a promising, though complex, therapeutic target for various cardiovascular diseases.

PMID:41009041 | PMC:PMC12466861 | DOI:10.3390/antiox14091137

Commun Biol. 2025 Sep 26;8(1):1368. doi: 10.1038/s42003-025-08742-0.

ABSTRACT

Phospholipase Cε (PLCε) cleaves phosphatidylinositol lipids to increase intracellular Ca2+ and activate protein kinase C (PKC) in response to stimulation of cell surface receptors. PLCε is activated via direct binding of small GTPases at the cytoplasmic leaflets of cellular membranes. In the cardiovascular system, the RhoA GTPase regulates PLCε to initiate a pathway that protects against ischemia/reperfusion injuries, but the underlying molecular mechanism is not known. We present here the cryo-electron microscopy (cryo-EM) reconstruction of RhoA bound to PLCε, showing that the G protein binds a unique insertion within the PLCε EF hands. Deletion of or mutations to this PLCε insertion decrease RhoA-dependent activation without impacting its regulation by other G proteins. Together, our data support a model wherein RhoA binding to PLCε allosterically activates the lipase and increases its interactions with the membrane, resulting in maximum activity and cardiomyocyte survival.

PMID:41006770 | PMC:PMC12475037 | DOI:10.1038/s42003-025-08742-0

Biochem Pharmacol. 2025 Sep 24;242(Pt 3):117366. doi: 10.1016/j.bcp.2025.117366. Online ahead of print.

ABSTRACT

Cardiac hypertrophy is a pathological adaptive response to chronic hemodynamic stress or injury, which may progress irreversibly to heart failure if left untreated. The objective of the study was to investigate whether inhibition of phosphodiesterase 5 can induce mitophagy to alleviate pathological cardiac hypertrophy. Sildenafil (Sif) effectively alleviates isoproterenol-induced cardiac hypertrophy in vivo by decreasing left ventricular wall thickness, reducing cardiac interstitial fibrosis, and improving cardiac functional parameters. Additionally, Sif protects against cardiomyocyte hypertrophy in vitro by lowering atrial natriuretic peptide levels and cardiomyocyte cross-sectional area. It also enhances mitochondrial function through the activation of PTEN-induced putative kinase-1 (PINK1)/Parkin-mediated mitophagy. Importantly, the autophagy inhibitor chloroquine abolished Sif-induced mitophagy and cardioprotection, thereby confirming the essential role of autophagic flux. Furthermore, the protective effects of Sif were reversed by the protein kinase G (PKG) inhibitor KT5823, indicating a dependence on the cyclic GMP (cGMP)-PKG signaling pathway. Altogether, Sif enhances mitophagy and maintain mitochondrial integrity by activating the PINK1/Parkin pathway through the cGMP-PKG signaling cascade, highlighting its potential to protect the myocardium perioperatively.

PMID:41005622 | DOI:10.1016/j.bcp.2025.117366

Pharmacol Res. 2025 Sep 24;221:107970. doi: 10.1016/j.phrs.2025.107970. Online ahead of print.

ABSTRACT

Fibrosis is a fundamental pathological process driving heart failure progression by promoting extracellular matrix deposition and impairing myocardial compliance. In recent years, the sirtuin family of NAD⁺-dependent deacetylases, traditionally linked to aging and metabolism, has emerged as a key regulator of cardiac fibrotic remodeling. This review investigates the roles of sirtuins in mitigating cardiac fibrosis, with emphasis on mechanisms such as mitochondrial preservation and the therapeutic potential of their modulation. Sirtuin signaling attenuates fibrosis by regulating intracellular pathways that control fibroblast activation. In particular, sirtuin-mediated deacetylation modulates pro-fibrotic mediators, including the TGF-β/Smad pathway, thereby reducing collagen synthesis and fibrotic gene expression. However, their effects are isoform- and context-dependent: SIRT1, SIRT3, SIRT6, and SIRT7 generally exert protective roles, whereas SIRT2 and SIRT5 may display neutral or even pro-fibrotic actions depending on the cell type, disease stage, and experimental context. Recognizing this complexity is essential to evaluate their therapeutic relevance. Building on these mechanistic insights, the review explores the preclinical development of sirtuin-targeted therapies. Strategies include NAD⁺ precursors, natural compounds, novel small-molecule activators with enhanced specificity, and agents that indirectly stimulate sirtuins through metabolic modulation. Such approaches highlight the potential of pharmacologically enhancing sirtuin activity to counteract maladaptive cardiac remodeling and improve outcomes in heart failure. By integrating molecular insights with advances in pharmacology, this review synthesizes the most recent mechanistic findings from the past three years with a dedicated focus on the translational challenges and opportunities of pharmacologically targeting sirtuins for anti-fibrotic therapy.

PMID:41005588 | DOI:10.1016/j.phrs.2025.107970

Phytomedicine. 2025 Sep 22;148:157294. doi: 10.1016/j.phymed.2025.157294. Online ahead of print.

ABSTRACT

BACKGROUND: Acute myocardial ischemia (AMI) carries a high risk of heart failure and subsequent mortality. However, current therapies remain limited by suboptimal drug efficacy and high costs, prompting exploration of alternative strategies, such as remote therapy. Capsaicin is a natural extract from red chili peppers. Remote therapy using it as the primary component has demonstrated efficacy in AMI treatment. However, this specific mechanism requires further exploration.

PURPOSE: Here, we investigate the therapeutic effects of remote capsaicin application therapy on AMI and elucidate the underlying neuro-immune interactions responsible.

METHODS AND RESULTS: We applied capsaicin cream to the ventral forelimb of rats, finding that it enhanced the sympathetic-sensory coupling (SSC) state in the skin and dorsal root ganglia (DRGs) (C8-T6), improving cardiac function over 28 days. Localized yohimbine (YOB) injections in skin /DRGs confirmed the critical role of the SSC structure. Mechanistically, capsaicin-enhanced SSC increased neuropeptide Y-positive (NPY+) nerve fiber density in peri‑infarct myocardium, concurrently shifting cardiac NPY receptor expression toward predominant NPY2R. Inhibiting cardiac NPY2R expression eliminated the functional benefits of capsaicin. In vitro co-culture of H9C2 cardiomyocytes and RAW264.7 cells showed functional NPY2R localization in cardiomyocytes. Activation of cardiomyocyte NPY2R promoted macrophages to secrete the anti-inflammatory factor IL-10, reducing hypoxia-induced cardiomyocyte apoptosis. Adeno-associated virus (AAV)-mediated overexpression of NPY2R in cardiomyocytes mimicked the cardioprotective effects of capsaicin. RNA sequencing revealed that NPY2R overexpression inhibited the IL-1β-induced NF-κB pathway in the heart. Flow cytometry confirmed these changes were due to reduced M1 macrophages and neutrophil infiltration in the infarct area.

CONCLUSION: Capsaicin enhances the segmental SSC structure to protect cardiac function in AMI rats, primarily associated with the improvement of the immune microenvironment induced by NPY+ nerve and NPY2R activation in the heart.

PMID:41005056 | DOI:10.1016/j.phymed.2025.157294

PLoS One. 2025 Sep 26;20(9):e0332862. doi: 10.1371/journal.pone.0332862. eCollection 2025.

ABSTRACT

This study aimed to investigate the potential compensatory role of plasma exosomal microRNAs (miRNAs), particularly miR-320b, in mitigating early myocardial damage in severe obstructive sleep apnea (OSA) patients without comorbidities. AC16 human cardiomyocytes were co-incubated with plasma exosomes isolated from healthy volunteers (Ctrl-exo) and patients with uncomplicated severe OSA (OSA-exo). Functional assays revealed that OSA-exo significantly enhanced AC16 cell viability, promoted proliferation, and reduced apoptosis. RNA sequencing (RNA-seq) identified 14 myocardial function-related mRNAs in AC16 cardiomyocytes differentially influenced by OSA-exo. Out of the 14 mRNAs, FOXM1, a critical regulator of cardiomyocyte stress response, survival, and regeneration, was verified to be upregulated by OSA-exo by RT-qPCR. Bioinformatic analysis predicted a regulatory relationship between miR-320b and FOXM1, which was confirmed by a dual-luciferase reporter assay. MiR-320b was found to be downregulated in OSA-exo by RT-qPCR. MiR-320b overexpression downregulated FOXM1, induced G0/G1 cell cycle arrest, reduced cell viability, and increased apoptosis. In a mouse model of chronic intermittent hypoxia (CIH), myocardial FOXM1 exhibited a biphasic expression pattern during disease progression. After 4 weeks of CIH exposure, the mouse myocardium exhibited significantly increased FOXM1 expression and reduced levels of apoptosis compared to control, suggesting an early compensatory response. However, after 12 weeks of CIH exposure, decreased myocardial FOXM1 expression and increased apoptosis were detected, suggesting that the early compensatory protective mechanism was overwhelmed by myocardial injury caused by chronic hypoxia, leading to enhanced cardiomyocyte apoptosis and consequent FOXM1 downregulation. These results suggested that miR-320b downregulation in OSA-exo may serve as a compensatory mechanism to protect against early myocardial injury through the upregulation of FOXM1, highlighting miR-320b and FOXM1 as potential therapeutic targets for OSA-associated cardiomyopathy.

PMID:41004495 | PMC:PMC12469182 | DOI:10.1371/journal.pone.0332862

Biosci Rep. 2025 Sep 23:BSR20253737. doi: 10.1042/BSR20253737. Online ahead of print.

ABSTRACT

FGR proto-oncogene (Fgr), a member of the Src family kinases, has garnered attention for its potential involvement in apoptotic signaling, yet its role in cardiovascular diseases, particularly acute myocardial infarction (AMI), remains unexplored. This study sought to investigate whether elevated left ventricular Fgr expression alleviates myocardial injury in the infarcted area and whether this protective mechanism is mediated by modulating phosphoinositide 3-kinase (PI3K)/Akt phosphorylation. The transcriptome-wide association study was initially utilized to screen for susceptibility genes in the left ventricle, with findings validated using bulk-RNA sequencing data from a rat model of left anterior descending coronary artery (LAD) ligation; subsequently, human spatial transcriptomics combined with single-nucleus RNA sequencing data confirmed differential expression of Fgr and PI3K/Akt in the infarcted region. Fgr knockdown via siRNA in H9C2 cells and pharmacological inhibition with TL02-59 in rats were conducted to assess cellular survival and cardiac function, respectively. Fgr emerged as a common candidate gene identified through multi-omics data analysis, with its up-regulation confirmed both in vivo and in vitro. Fgr silencing in an in vitro oxygen-glucose deprivation model significantly reduced cell survival and suppressed PI3K/Akt phosphorylation, whereas TL02-59 administration in rats subjected to LAD ligation impaired post-infarction cardiac function while concurrently inhibiting PI3K/Akt phosphorylation levels. This study demonstrates that Fgr is markedly up-regulated in AMI and exerts cardioprotective effects, possibly through modulation of PI3K/Akt signaling phosphorylation, thereby underscoring its potential as a therapeutic target.

PMID:41004172 | DOI:10.1042/BSR20253737

J Cardiovasc Dev Dis. 2025 Aug 28;12(9):329. doi: 10.3390/jcdd12090329.

ABSTRACT

The possible protective effect of obesity in the outcomes of chronic kidney disease (CKD) patients is an understudied field. We aimed to evaluate the prognostic value of vascular calcification (VC) on long-term outcomes in obese and non-obese CKD patients. We conducted a single-centre, prospective observational study of 150 CKD patients. Patients were divided into two groups using body mass index (BMI) scores (BMI ≥ 30 kg/m2 and BMI < 30 kg/m2). Lateral lumbar X-rays (Kauppila score), the ankle-brachial index (ABI), and echocardiography were used for assessing VC. By the 11.2-year follow-up, 70 patients had died (47%). Twenty-four patients had had CV complications: stroke, myocardial infarction, decompensated heart failure, amputation caused by atherosclerosis, and aortic rupture. Among obese patients (BMI ≥ 30 kg/m2), only LVH was a significant predictor of CV complications (p = 0.01) and mortality (p = 0.004). In patients with BMI < 30 kg/m2, predictors of CV complications and mortality were ABI (p = 0.03; p = 0.009), LVH (p = 0.02 for CV complications) and heart valve lesions (p = 0.009; p = 0.004). There were no differences in the measured parameters of VC between the obese and non-obese groups. Moreover, no significant differences were found comparing patients with and without obesity according to the studied parameters; we found no significant differences in complications and mortality. VC in patients with CKD is a significant complication that negatively impacts outcomes. Obesity does not have a protective effect in long-term outcomes in CKD patients.

PMID:41002608 | PMC:PMC12470804 | DOI:10.3390/jcdd12090329