Cordycepin ameliorates cardiac hypertrophy via activating the AMPKα pathway.

Increase of myocardial oxidative stress is closely related to the occurrence and development of cardiac hypertrophy. Cordycepin, also known as 3'-deoxyadenosine, is a natural bioactive substance extracted from Cordyceps militaris (which is widely cultivated for commercial use in functional foods and medicine). Since cordycepin suppresses oxidative stress both in vitro and in vivo, we hypothesized that cordycepin would inhibit cardiac hypertrophy by blocking oxidative stress-dependent related signalling. In our study, a mouse model of cardiac hypertrophy was induced by aortic banding (AB) surgery. Mice were intraperitoneally injected with cordycepin (20 mg/kg/d) or the same volume of vehicle 3 days after-surgery for 4 weeks. Our data demonstrated that cordycepin prevented cardiac hypertrophy induced by AB, as assessed by haemodynamic parameters analysis and echocardiographic, histological and molecular analyses. Oxidative stress was estimated by detecting superoxide generation, superoxide dismutase (SOD) activity and malondialdehyde levels, and by detecting the protein levels of gp91phox and SOD. Mechanistically, we found that cordycepin activated activated protein kinase α (AMPKα) signalling and attenuated oxidative stress both in vivo in cordycepin-treated mice and in vitro in cordycepin treated cardiomyocytes. Taken together, the results suggest that cordycepin protects against post-AB cardiac hypertrophy through activation of the AMPKα pathway, which subsequently attenuates oxidative stress.

Oridonin protects against cardiac hypertrophy by promoting P21-related autophagy.

Autophagy is an endogenous protective process; the loss of autophagy could destabilize proteostasis and elevate intracellular oxidative stress, which is critically involved in the development of cardiac hypertrophy and heart failure. Oridonin, a natural tetracycline diterpenoid from the Chinese herb Rabdosia, has autophagy activation properties. In this study, we tested whether oridonin protects against cardiac hypertrophy in mice and cardiomyocytes. We implemented aortic banding to induce a cardiac hypertrophy mouse model, and oridonin was given by gavage for 4 weeks. Neonatal rat cardiomyocytes were stimulated with angiotensin II to simulate neurohumoural stress. Both in vivo and in vitro studies suggested that oridonin treatment mitigated pressure overload-induced cardiac hypertrophy and fibrosis, and also preserved heart function. Mice that received oridonin exhibited increased antioxidase activities and suppressed oxidative injury compared with the aortic banding group. Moreover, oridonin enhanced myocardial autophagy in pressure-overloaded hearts and angiotensin II-stimulated cardiomyocytes. Mechanistically, we discovered that oridonin administration regulated myocardial P21, and cytoplasmic P21 activated autophagy via regulating Akt and AMPK phosphorylation. These findings were further corroborated in a P21 knockout mouse model. Collectively, pressure overload-induced autophagy dysfunction causes intracellular protein accumulation, resulting in ROS injury while aggravating cardiac hypertrophy. Thus, our data show that oridonin promoted P21-related autophagic lysosomal degradation, hence attenuating oxidative injury and cardiac hypertrophy.

Galangin ameliorates cardiac remodeling via the MEK1/2-ERK1/2 and PI3K-AKT pathways.

Cardiac remodeling is associated with inflammation and apoptosis. Galangin, as a natural flavonol, has the potent function of regulating inflammation and apoptosis, which are factors related to cardiac remodeling. Beginning 3 days after aortic banding (AB) or Sham surgery, mice were treated with galangin for 4 weeks. Cardiac remodeling was assessed according to echocardiographic parameters, histological analyses, and hypertrophy and fibrosis markers. Our results showed that galangin administration attenuated cardiac hypertrophy, dysfunction, and fibrosis response in AB mice and angiotensin II-treated H9c2 cells. The inhibitory action of galangin in cardiac remodeling was mediated by MEK1/2-extracellular-regulated protein kinases 1/2 (ERK1/2)-GATA4 and phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-glycogen synthase kinase 3ß (GSK3ß) activation. Furthermore, we found that galangin inhibited inflammatory response and apoptosis. Our findings suggest that galangin protects against cardiac remodeling through decreasing inflammatory responses and apoptosis, which are associated with inhibition of the MEK1/2-ERK1/2-GATA4 and PI3K-AKT-GSK3ß signals.

Isoquercitrin Attenuated Cardiac Dysfunction Via AMPKα-Dependent Pathways in LPS-Treated Mice.

SCOPE: Isoquercitrin (IQC) has been reported to play a protective role in many pathological conditions. Here, the effects of IQC on lipopolysaccharide (LPS)-induced cardiac dysfunction are investigated, exploring its potential molecular mechanisms. METHODS AND RESULTS: C57BL/6 mice or H9c2 cardiomyoblasts are subjected to LPS challenge for 12 h. Pretreatment with IQC attenuates LPS-induced cardiac dysfunction. IQC remarkably reduces LPS-mediated inflammatory responses by inhibiting the mRNA levels of TNF-α, IL6, and MCP1 as well as the protein levels of p-IKKß, p-IκBα, and p-p65 in vivo and in vitro. Interestingly, IQC administration also improves energy deficiencies caused by LPS, manifesting as significant increases in cardiac and cellular ATP levels. Furthermore, ATP levels increase due to the upregulation of PGC1ß and PPAR-α, which enhances fatty acid oxidation in vivo and in vitro. However, the protective roles of IQC against LPS-mediated increased inflammatory responses and decreased acid fatty oxidation are partially blunted by inhibiting AMPKα in vitro, and suppressing AMPKα partially blocks the increased cardiac function elicited by IQC in LPS-treated mice. CONCLUSION: IQC attenuates LPS-induced cardiac dysfunction by inhibiting inflammatory responses and by enhancing fatty acid oxidation, partially by activating AMPKα. IQC might be a potential drug for sepsis-induced cardiac dysfunction.

Role of autophagy in a model of obesity: A long­term high fat diet induces cardiac dysfunction.

Obesity may induce end­organ damage through metabolic syndrome, and autophagy serves a vital role in the pathogenesis of metabolic syndrome. The purpose of the present study was to define the roles of autophagy and mitophagy in high fat diet (HFD)­induced cardiomyopathy. Male, 8 week­old C57BL/6 mice were fed either a HFD (60% kcal) or a diet of normal chow (NC; 10% kcal) for 42 weeks. Glucose tolerance tests were performed during the feeding regimes. Blood samples were collected for assaying serum triglyceride with the glycerol­3­phosphate oxidase phenol and aminophenazone (PAP) method and total cholesterol was tested with the cholesterol oxidase­PAP method. Myocardial function was assessed using echocardiography and hemodynamic analyses. Western blot analysis was employed to evaluate endoplasmic reticulum stress (ERS), autophagy and mitochondrial function. Electron microscopy was used to assess the number of lipid droplets and the degree of autophagy within the myocardium. The body weight and adipose tissue weight of mice fed the HFD were increased compared with the NC mice. The serum levels of blood glucose, total cholesterol and triglyceride were significantly increased following 42 weeks of HFD feeding. The results of the glucose tolerance tests additionally demonstrated metabolic dysregulation in HFD mice. In addition, HFD mice exhibited hemodynamic and echocardiographic evidence of impaired diastolic and systolic function, including alterations in the cardiac output, end­diastolic pressure, end­diastolic volume and left ventricular relaxation time constant (tau) following HFD intake. Furthermore, a HFD resulted in increased ERS, and a downregulation of the autophagy and mitophagy level. The present study investigated cardiac function in obese HFD­fed mice. These results aid the pursuit of novel therapeutic targets to combat obesity­associated cardiomyopathy.

Baicalein protects against endothelial cell injury by inhibiting the TLR4/NF­κB signaling pathway.

The involvement of vascular endothelial injury with the pathophysiological process of heart failure has been identified. Baicalein (BAI), a flavonoid extracted from the root of Scutellaria baicalensis, is reported to exert antibacterial, antiviral, antithrombotic and antioxidant effects. The aim of the present study was to investigate the effects of BAI on lipopolysaccharide (LPS)­induced vascular endothelial injury. Human umbilical vein endothelial cells (HUVECs) were stimulated by LPS (10 µM) in the presence or absence of BAI. The expressions of the inflammatory cytokines interleukin (IL)­lß, IL­6, tumor necrosis factor­α (TNF­α) and monocyte chemoattractant protein­1 (MCP­1) were analyzed by reverse transcription­quantitative polymerase chain reaction, western blotting and enzyme­linked immunosorbent assay. Cell apoptosis was assessed by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The results showed that BAI significantly inhibited the LPS­induced inflammatory response and apoptosis in HUVECs. BAI suppressed the LPS­induced upregulation of IL­1ß, IL­6, TNF­α and MCP­1. Furthermore, BAI decreased the expression of B­cell lymphoma 2 (Bcl­2)­associated X protein and cleaved caspase­3; however, it increased the protein level of Bcl­2. The inhibitory effect of BAI may occur through the suppression of the Toll­like receptor 4 (TLR4)/phosphorylated (p)­transforming growth factor ß­activated kinase 1/tumor necrosis factor receptor­associated family member associated nuclear factor (NF)­κB activator­binding kinase 1 (p­TBK1)/NF­κB signaling pathway. An increase in the level of p­TBK1 by MRT67307 abolished the effect of BAI on p­p65. In conclusion, the results of the present research suggested that BAI ameliorated endothelial cell injury associated with TLR4/NF­κB signaling, and highlighted the potential clinical use of BAI in blocking endothelial dysfunction and preventing heart failure.

Arctiin protects against cardiac hypertrophy through inhibiting MAPKs and AKT signaling pathways.

PURPOSE: The mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) pathways have emerged as essential intracellular signaling pathways in eukaryotic cells, particularly as regulators of cardiac hypertrophy. Previous studies indicated that arctiin, an active ingredient of biennial dried ripe burdock, could exhibit potent anti-inflammatory and anti-allergic activities via down-regulating the activation of MAPKs and AKT pathways. However, little is known about its effects on cardiac hypertrophy. Therefore, the present study aimed to explore whether arctiin could attenuate cardiac hypertrophy. GENERAL METHODS: Arctiin (80 mg/kg) was administered by oral gavage once daily for 3 weeks from 1 week after surgery. Then, the mice were subjected to either chronic pressure overload generated by aortic banding (AB) or sham surgery (control group). Cardiac function was assessed by echocardiography. FINDINGS: The results indicated that arctiin attenuated cardiac hypertrophy induced by AB, and suppressed cardiac fibrosis and accumulation of collagen in vivo. Arctiin also inhibit the activation of MAPKs and AKT occurs in response to hypertrophic stimuli. Arctiin attenuated phenylephrine-induced hypertrophy of myocytes in vitro. CONCLUSIONS: In conclusion, arctiin can improve cardiac function and prevent the development of cardiac hypertrophy by blocking the MAPKs and AKT signaling pathways.