Heart failure (HF) is a leading cause of hospitalization across the world and is known to cause ill-health and heavy economic losses. In the present study, a rat model of isoproterenol (ISO, 85 mg/kg subcutaneously for two subsequent days) induced HF was developed. ISO induces HF by its direct effect, that is, rise in left ventricular end-diastolic pressure (mechanical) and indirectly by altering the baroreflex (neural), electrocardiography (electrical), and development of oxidative stress and hyperlipidemia (chemical). Fenofibrate, a hypolipidemic drug, which ameliorates myocardial energy metabolism was seen to improve the both ISO-induced oxidative stress and lipid profile and consequently improved Baroreflex Sensitivity (BRS), partial ventricular functions, and cardiac hypertrophy. Therefore, our result suggests that fenofibrate treatment protected the heart by alleviating the ISO-induced effects, that is, neural, mechanical, electrical, and chemical alterations.

Background: Aging elevates reactive oxygen species (ROS) and weakens antioxidant defenses, contributing to cardiac dysfunction. The objective of this study was to determine whether sustained activation of skeletal muscle (SkM) Nrf2 preserves cardiac function during aging and to explore the underlying mechanisms, focusing on myocardial antioxidant pathways. Methods: Tamoxifen-induced SkM-specific Keap1 knockout male mice (iMS-Keap1^flox/flox; SkM-Nrf2 overexpression) were divided into young wild-type (Y-WT), aged wild-type (A-WT), and aged knockout (A-KO) groups. Cardiac performance was evaluated by echocardiography and invasive hemodynamics. Myocardial proteomics identified differentially expressed proteins (DEPs) and enriched biological pathways. Results: Compared with Y-WT, A-WT mice showed impaired left ventricular function, including reduced ejection fraction, prolonged isovolumic relaxation time, blunted inotropic response to dobutamine, and elevated Tau index. These age-related deficits were partially reversed in A-KO mice. Proteomic analysis revealed 561 DEPs between A-WT and Y-WT, and 741 DEPs between A-KO and A-WT, enriched in calcium signaling, Nrf2-mediated oxidative stress response, oxidative phosphorylation, ROS detoxification, and cardiac-specific processes, such as hypertrophy, conduction, and dilated cardiomyopathy. Conclusions: Lifelong SkM-Nrf2 activation strengthens myocardial antioxidant capacity and alleviates age-related cardiac dysfunction. These data support an antioxidant crosstalk between skeletal muscle and the heart, highlighting a potential therapeutic target for aging-associated heart failure.

Objective: This study aims to explore the role of estrogen in providing cardioprotective benefits to premenopausal women, examining how hormonal differences between sexes influence the prevalence of cardiovascular diseases (CVDs) in women. Materials and methods: Eighteen female Wistar rats were equally distributed into three treatment groups. Animals in Group I (sham-operated) and Group II (ovariectomized [OVX]) received oral saline solution at a dose of 2 mL/kg. Group III (OVX+E2) received oral E2 2 µg/mL/kg after ovariectomy. Hemodynamic parameters and [...] ABSTRACT Objective: This study aims to explore the role of estrogen in providing cardioprotective benefits to premenopausal women, examining how hormonal differences between sexes influence the prevalence of cardiovascular diseases (CVDs) in women. Materials and methods: Eighteen female Wistar rats were equally distributed into three treatment groups. Animals in Group I (sham-operated) and Group II (ovariectomized [OVX]) received oral saline solution at a dose of 2 mL/kg. Group III (OVX+E2) received oral E2 2 µg/mL/kg after ovariectomy. Hemodynamic parameters and

Cognitive impairment (CI) is prevalent among heart failure (HF) patients. Although the brain injury in HF is multifactorial, oxidative stress and neuroinflammation are common pathological features of neurological disorders and are increasingly recognized as key mechanisms underlying CI. Extracellular vesicles (EVs) are well-established mediators of biological signaling in myocardial function and are widely recognized for transporting a variety of microRNAs. However, whether myocardial injury alters the miRNA profiles of brain EVs, potentially contributing to cognitive impairment (CI) by disrupting brain homeostasis, remains poorly understood. Using a rodent myocardial infarction (MI) model, we isolated brain EVs and characterized their miRNA profiling by means of small RNA sequencing. Our results demonstrate that miRNA profiles in brain EVs vary with HF progression. Only three miRNAs were significantly changed at 3 weeks post-MI, whereas thirty-two miRNAs and sixty-five miRNAs demonstrated significant changes post-MI, showed significant alterations at 6 and 12 weeks post-MI, respectively. Bioinformatic analysis suggests that some miRNAs against oxidative stress and inflammation were downregulated in brain EVs at 6 and 12 weeks post-MI. Conversely, several miRNAs responsible for oxidative stress and neuroinflammation were significantly increased, which may be of cardiac origin following MI. Collectively, these findings suggest that cardiac EVs may contribute to miRNA alterations in brain EVs, potentially driving CI by disrupting brain homeostasis.

Cognitive impairment (CI) is prevalent among heart failure (HF) patients. Although the brain injury in HF is multifactorial, oxidative stress and neuroinflammation are common pathological features of neurological disorders and are increasingly recognized as key underlying mechanisms of CI. The role of extracellular vesicles (EVs) as effective communicators of biological signaling in myocardial function has been extensively investigated. EVs are well-known to transport a variety of microRNAs (miRNAs), however, it is unclear if myocardial injury alters the miRNA profiling of brain EVs which may contribute to CI by disrupting brain homeostasis. Using a rodent myocardial infarction (MI) model, we isolated brain EVs, and characterized their miRNA profiling by small RNA sequencing. Our results demonstrate that miRNA profiling in brain EVs varies with the progression of HF. Only three miRNAs were significantly changed at 3wks post-MI, thirty-two miRNAs demonstrate significant changes at 6wks post-MI, and sixty-five miRNAs show significant alterations at 12wks post-MI. Bioinformatic analysis suggests that some miRNAs against oxidative stress and inflammation were downregulated in brain EVs following 6wks post-MI, whereas several miRNAs responsible for oxidative stress and neuroinflammation were significantly increased, which may be cardiac in origin following MI. Collectively, cardiac EVs may contribute to the miRNA alterations in brain EVs, potentially contributing to CI by disrupting brain homeostasis.

Chronic heart failure (CHF) is a growing global health concern characterized, in part, by progressive sympathetic overactivation, which exacerbates this condition. Accumulating evidence identifies oxidative stress as a key driver of sympatho-excitation, mediated by excess reactive oxygen species (ROS) and impaired antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) is a central regulator of antioxidant gene expression, but its role in the peripheral sympathetic nervous system, particularly in the stellate ganglia, remains unclear. We hypothesized that Nrf2 signaling is disrupted in the stellate ganglia in CHF and that modulation of Nrf2 alters ROS levels and sympathetic responses. In rats, six weeks post myocardial infarction (MI), the stellate ganglia exhibited increased ROS levels in tyrosine hydroxylase-positive neurons along with reduced Nrf2 protein and mRNA expression; both changes were inversely associated with ejection fraction (EF). To determine the functional role of Nrf2, lentiviral vectors encoding GFP or GFP-Nrf2 were delivered to the stellate ganglia three weeks after MI. Nrf2 upregulation attenuated heart rate responses to stellate stimulation in sham rats but augmented responses in CHF rats. The increase in plasma norepinephrine levels was reduced following stellate stimulation in CHF rats that overexpressed Nrf2, while β1-adrenergic responsiveness to dobutamine was unchanged. This study demonstrates that CHF is associated with increased oxidative stress and reduced Nrf2 expression in the stellate ganglion. Nrf2 overexpression significantly modulated sympathetic regulation, altering heart rate responses and reducing plasma norepinephrine in CHF rats. These findings support the concept that impaired Nrf2 signaling contributes to ganglionic redox imbalance and dysregulated sympathetic nerve activity in CHF.