Sustained cardiac hypertrophy is a major cause of heart failure (HF) and death. Recent studies have demonstrated that resveratrol (RES) exerts a protective role in hypertrophic diseases. However, the molecular mechanisms involved are not fully elucidated. In this study, cardiac hypertrophic remodeling in mice were established by pressure overload induced by transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiography and invasive pressure-volume analysis. Cardiomyocyte size was detected by wheat germ agglutinin staining. The protein and gene expressions of signaling mediators and hypertrophic markers were examined. Our results showed that administration of RES significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and apoptosis and improved in vivo heart function in mice. RES also reversed pre-established hypertrophy and restoring contractile dysfunction induced by chronic pressure overload. Moreover, RES treatment blocked TAC-induced increase of immunoproteasome activity and catalytic subunit expression (β1i, β2i and β5i), which inhibited PTEN degradation thereby leading to inactivation of AKT/mTOR and activation of AMPK signals. Further, blocking PTEN by the specific inhibitor VO-Ohpic significantly attenuated RES inhibitory effect on cardiomyocyte hypertrophy in vivo and in vitro. Taken together, our data suggest that RES is a novel inhibitor of immunoproteasome activity, and may represent a promising therapeutic agent for the treatment of hypertrophic diseases.

Scope Gallic acid (GA) is a dietary phenolic acid found in tea, red wine, and some plants. It exhibits anti‐oxidative and anti‐inflammatory activities. Recent studies have revealed that GA has beneficial effects against several cardiovascular diseases; however, whether GA attenuates pressure‐overload‐induced cardiac hypertrophy and the underlying mechanism remains unclear. Methods and results Primary cardiomyocyte hypertrophy is stimulated with angiotensin II (Ang II). Cardiac hypertrophic remodeling is induced in mice by transverse aortic constriction (TAC). Myocardial function is evaluated by echocardiographic and hemodynamic analyses, while cardiac tissues are analyzed by histological staining. It is observed that GA significantly decreases Ang II‐induced increases in cardiomyocyte size in vitro. Administration of GA in mice markedly improves TAC‐induced cardiac dysfunction and attenuates pathological changes, including cardiac myocyte hypertrophy, fibrosis, inflammation, and oxidative stress. Mechanistically, GA inhibits ULK1 and activates autophagy, which induces the degradation of EGFR, gp130, and calcineurin A, thereby inhibiting the downstream signaling cascades (AKT, ERK1/2, JAK2/STAT3, and NFATc1). Conclusions The results demonstrate for the first time that GA prevents myocardial hypertrophy and dysfunction via an autophagy‐dependent mechanism. Thus, GA represents a promising therapeutic candidate for treating cardiac hypertrophy and heart failure.

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ScopeCardiac fibrosis is a key feature of cardiac remodeling. Recently, a protective role for resveratrol (RES) in pressure‐overload‐induced cardiac hypertrophy and contractile dysfunction has been demonstrated. However, the effect of RES on cardiac fibrosis and diastolic function in this model remains unclear.Methods and resultsCardiac remodeling is induced in mice by transverse aortic constriction (TAC) for 2–4 weeks. RES is administered at dose of 5 or 50 mg kg–1 d–1 for 2 weeks. It is found that RES administration at 50 mg kg–1 d–1 significantly attenuates TAC‐induced adverse cardiac systolic and diastolic function, fibrosis, inflammation, and oxidative stress via inhibiting PTEN degradation and the downstream mediators. However, RES at 5 mg kg–1 d–1 has no significant effects. RES at 50 mg kg–1 d–1 also ameliorates pre‐established adverse cardiac function and remodeling induced by TAC. Treatment with PTEN inhibitor VO‐OHpic (10 mg kg–1 d–1) for 2 weeks abolishes RES‐mediated protective effects. Additionally, the effect of RES (100 µm) on inhibition of Ang II‐induced fibroblast proliferation and activation in vitro is verified.ConclusionsThe findings provide new evidence that RES plays a critical role in the progression of cardiac fibrosis and diastolic dysfunction, and suggest that RES may be a promising therapeutic agent for cardiac fibrosis.

Background/Aim: Angiotensin II (Ang II) and hypertension play critical roles in the pathogenesis of the atrial remodeling that contributes to atrial fibrillation (AF). However, the gene expression profiles and signaling pathways in atria during the development of AF induced by Ang II remain unknown. Methods: Wild-type male mice (C57BL/6 background, 10 weeks old) were administered an infusion of Ang II (2000 ng/kg/min) using an osmotic pump for 1, 2, and 3 weeks. Blood pressure (BP) was measured by the tail-cuff method. AF was induced and recorded. Atrial enlargement and remodeling were examined by echocardiography and Masson’s trichrome staining. Time-series microarray analyses were conducted to examine gene expression profiles and pathways. Results: Ang II infusion resulted in marked elevation of systolic BP, increased AF incidence and duration, atrial enlargement, fibrosis, and atrial infiltration of myofibroblasts and F4/80-positive macrophages in a time-dependent manner. Microarray results showed that 1,719 genes were differentially expressed in the atrium at weeks 1, 2, and 3 after Ang II infusion. Gene ontology showed that these genes participate mainly in immune system processes, and regulation of cell migration, cell adhesion, complement activation, and the inflammatory response. Significant pathways included lysosomal and phagosomal pathways, which are involved in antigen processing and presentation, as well as chemokine signaling, and extracellular matrix–receptor interaction, which are known to play important roles in Ang II-induced AF. Moreover, these differentially expressed genes were classified into 50 profiles by hierarchical cluster analysis. Of these, eight profiles were significant and contained a total of 1,157 genes. Gene co-expression network analysis identified that Pik3cg (also known as phosphoinositide-3-kinase regulatory subunit 3) was localized in the core of the gene network, and was the most highly expressed among the Pik3 isoforms at different time points. Conclusion: The present findings revealed that many genes are involved in Ang II-induced AF, and highlighted that Pik3cg may play a central role in this disease.

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