Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1ß: In vivo and in vitro studies.

Melatonin, a circadian molecule secreted by the pineal gland, confers a protective role against cardiac hypertrophy induced by hyperthyroidism, chronic hypoxia, and isoproterenol. However, its role against pressure overload-induced cardiac hypertrophy and the underlying mechanisms remains elusive. In this study, we investigated the pharmacological effects of melatonin on pathological cardiac hypertrophy induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or sham surgery at day 0 and were then treated with melatonin (20 mg/kg/day, via drinking water) for 4 or 8 weeks. The 8-week survival rate following TAC surgery was significantly increased by melatonin. Melatonin treatment for 8 weeks markedly ameliorated cardiac hypertrophy. Compared with the TAC group, melatonin treatment for both 4 and 8 weeks reduced pulmonary congestion, upregulated the expression level of α-myosin heavy chain, downregulated the expression level of ß-myosin heavy chain and atrial natriuretic peptide, and attenuated the degree of cardiac fibrosis. In addition, melatonin treatment slowed the deterioration of cardiac contractile function caused by pressure overload. These effects of melatonin were accompanied by a significant upregulation in the expression of peroxisome proliferator-activated receptor-gamma co-activator-1 beta (PGC-1ß) and the inhibition of oxidative stress. In vitro studies showed that melatonin also protects against angiotensin II-induced cardiomyocyte hypertrophy and oxidative stress, which were largely abolished by knocking down the expression of PGC-1ß using small interfering RNA. In summary, our results demonstrate that melatonin protects against pathological cardiac hypertrophy induced by pressure overload through activating PGC-1ß.

Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1.

Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.

The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway.

In this study, we evaluated the effect of curcumin (Cur) post-treatment on isolated perfused rat hearts that had been subjected to a protocol of ischemia and reperfusion injury. We also examined whether the Janus kinase 2 and signal transducer and activator 3 of transcription (JAK2/STAT3) signaling pathway plays a role in the cardioprotective effects of Cur post-treatment. Isolated perfused rat hearts were subjected to 60 min of ischemia, followed by 60 min of reperfusion. The hearts were exposed to 1-µM Cur during the first 10 min of reperfusion in the absence or presence of the JAK kinase-specific inhibitor AG490 (AG, 1 µM). The Cur treatment conferred a cardioprotective effect, and the treated hearts demonstrated an improved post-ischemic cardiac functional recovery, a decreased myocardial infarct size and decreased lactate dehydrogenase release in the coronary flow, a reduced number of apoptotic cardiomyocytes, up-regulation of the anti-apoptotic protein Bcl2 and down-regulation of the pro-apoptotic protein Caspase3. AG blocked the Cur-mediated cardioprotection by inhibiting the JAK2/STAT3 signaling pathway, as reflected by the abrogation of the Cur-induced up-regulation of Bcl2 and down-regulation of Caspase3. The results suggest that Cur post-treatment can attenuate IR injury through the activation of the JAK2/STAT3 signaling pathway, which transmits a survival signal to the myocardium.

Protective effects of hyperoside against human umbilical vein endothelial cell damage induced by hydrogen peroxide.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperoside (Hyp) is a flavonoid compound isolated from Rhododendron ponticum L. leaves that elicits vascular protective effects in vitro. Treatment with Hyp has been found to attenuate endothelial cell damage induced by oxidative stress, but its mechanisms of action remain unclear. This study investigated the action of Hyp in an endothelial injury model induced by hydrogen peroxide (H(2)O(2)), as well as its possible mechanisms. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with H(2)O(2) alone or in combination with Hyp. The protective effects of Hyp against H(2)O(2) were evaluated, and the activation of extracellular signal-regulated protein kinase (ERK) in Hyp was assayed in HUVECs. RESULTS: Loss of cell viability as well as excessive cell apoptosis and death were observed in HUVECs after 18 h of challenge with H(2)O(2) (400µM); however, both cell apoptosis and death were attenuated in the Hyp-pretreated cells. Western blot analysis revealed that Hyp increased the expression of Bcl-2 but decreased that of Bax. In addition, Hyp induced the phosphorylation of ERK1/2 in HUVECs. CONCLUSION: These observations provide preliminary evidence that Hyp protects HUVECs against H(2)O(2) damage, at least partially, by activating the ERK signaling pathway.

α-Linolenic acid intake attenuates myocardial ischemia/reperfusion injury through anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats.

BACKGROUND AND AIMS: Patients with diabetes show enhanced susceptibility to myocardial ischemia/reperfusion (MI/R) injury. Epidemiological studies indicated that consumption of α-linolenic acid (ALA) significantly reduces the risk of cardiac events in post-acute myocardial infarction patients. The present study attempted to investigate the effects of ALA intake on MI/R injury in normal and diabetic rats and its mechanisms. METHODS: The high-fat diet-fed streptozotocin (HFD-STZ) rat model was developed. Age-matched normal and HFD-STZ rats were randomly assigned to receive normal diet or ALA (oral gavage, 500 µg/kg per day). After 4 weeks of feeding, animals were subjected to 30 min of myocardial ischemia and 4 or 6 h of reperfusion. RESULTS: Compared with the normal control, HFD-STZ rats showed more severe myocardial functional impairment and injury. Although ALA intake for 4 weeks did not change myocardial function and injury in normal rats, it significantly improved the instantaneous first derivation of left ventricle pressure, reduced infarct size, plasma creatine kinase and lactate dehydrogenase activities, and apotosis at the end of reperfusion in HFD-STZ diabetic rats. Moreover, ALA intake not only significantly reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations but reduced the increase in superoxide production and malonaldialdehyde formation and simultaneously enhanced the antioxidant capacity in the diabetic hearts. Myocardial PI3K expression and Akt phosphorylation were increased by ALA intake in diabetic but not normal rats. CONCLUSIONS: Chronic ALA intake confers cardioprotection in MI/R by exerting anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats, which is possibly through PI3K-Akt-dependent mechanism.