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Achyranthes bidentata, a Chinese medicinal herb, is reported to be neuroprotective. However, its role in cardioprotection remains largely unknown. Our present study aimed to investigate the effects of Achyranthes bidentata polypeptides (ABPP) preconditioning on myocardial ischemia/reperfusion (MI/R) injury and to test the possible mechanisms. Rats were treated with ABPP (10 mg/kg/d, i.p.) or saline once daily for one week. Afterward, all the animals were subjected to 30 min of myocardial ischemia followed by 4 h of reperfusion. ABPP preconditioning for one week significantly improved cardiac function following MI/R. Meanwhile, ABPP reduced infarct size, plasma creatine kinase (CK)/lactate dehydrogenase (LDH) activities and myocardial apoptosis at the end of reperfusion in rat hearts. Moreover, ABPP preconditioning significantly inhibited superoxide generation, gp91phox expression, malonaldialdehyde formation and enhanced superoxide dismutase activity in I/R hearts. Furthermore, ABPP treatment inhibited PTEN expression and increased Akt phosphorylation in I/R rat heart. PI3K inhibitor wortmannin blocked Akt activation, and abolished ABPP-stimulated anti-oxidant effect and cardioprotection. Our study demonstrated for the first time that ABPP reduces oxidative stress and exerts cardioprotection against MI/R injury in rats. Inhibition of PTEN and activation of Akt may contribute to the anti-oxidant capacity and cardioprotection of ABPP.

Context: Peroxynitrite (ONOO(-)) formation triggers oxidative/nitrative stress and contributes to exacerbated myocardial ischemia/reperfusion (MI/R) injury. Catalpol, an iridoid glycoside, abundantly found in the roots of Rehmannia glutinosa L. that is included in the family Phrymaceae in the order Lamiales, endemic to China, was found to have neuroprotective effects. However, the effect of catalpol on MI/R injury has not been identified., Objective: This study investigated whether catalpol attenuates oxidative/nitrative stress in acute MI/R., Materials and Methods: Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion and were treated with saline, catalpol (5 mg/kg, i.p., 5 min before reperfusion) or catalpol plus wortmannin (15 µg/kg intraperitoneally injected 15 min before reperfusion)., Results: Pretreatment with catalpol significantly improved cardiac functions, reduced myocardial infarction, apoptosis and necrosis of cardiomyocytes after MI/R (all p < 0.05). Meanwhile, ONOO(-) formation was markedly reduced after catalpol treatment (3.01 ± 0.22 vs. 4.66 ± 0.53 pmol/mg protein in vehicle, p < 0.05). In addition, catalpol increased Akt and endothelial nitric oxide synthase phosphorylation, nitric oxide (NO) production, anti-oxidant capacity and reduced MI/R-induced inducible nitric oxide synthase expression and superoxide anion (·O(2)(-)) production in I/R hearts. PI3K inhibitor wortmannin not only blocked catalpol-induced Akt activation, but also attenuated all the beneficial effects of catalpol. Suppression of ONOO(-) formation by either catalpol or an ONOO(-) scavenger uric acid (5 mg/kg) reduced myocardial infarct size in MI/R rats., Discussion and Conclusion: In conclusion, catalpol affords cardioprotection against MI/R insult by attenuating ONOO(-) formation, which is attributable to increased physiological NO and decreased ·O(2)(-) production.

Metabolic syndrome is well known to increase the risk of cardiovascular disease and diabetes. As the key feature of metabolic syndrome, insulin resistance occurs when target tissues cannot respond properly to insulin and develops in multiple organs, including the vasculature and heart. Accumulating evidence has suggested insulin-induced PI3K-Akt-eNOS survival signaling as a potent therapeutic target for cardiovascular disorders and highlighted the impaired survival signaling as a key link between insulin resistance and cardiovascular disease. However, long-term insulin treatment is inconvenient and may increase the risk of hypoglycemia. More importantly, the effects of insulin are significantly blunted in patients with insulin resistance due to the pathway-specific impairment of PI3K-Akt signaling, and exogenous chronic insulin administration may lead to the over-activation of Ras-MAPK signaling which may result in unwanted side effects. Our recent study has shown that some Chinese medicinal herbs can directly activate PI3K-Akt-eNOS survival signals and improve tissue insulin sensitivity to exert endothelial and cardiac protective effects in diabetic animals. These herbs or phytoinsulins as we named, targeting insulin-activated cell survival signals and exert insulin-like actions, have promising beneficial effects on prevention and treatment of diabetes- and insulin resistance-induced cardiovascular disorders. Another advantage of phytoinsulins is that they generally exert multiple actions, including mild blood glucose-lowering effect, pancreatic β cells protection and adipogenesis reduction, for better cardiovascular protection. In this review, we discussed our strategies of searching for phytoinsulins and their potential beneficial effects in the treatment of metabolic syndrome, especially their values in prevention of diabetic cardiovascular disease.

Aims: Ischemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury. Methods: Normal or streptozotocin (STZ)-treated diabetic rats subjected to 2 cycles of 5 min ischemia/5 min reperfusion prior to myocardial ischemia (30 min)/reperfusion (3 h). Myocardial glucose uptake was determined by 18F-fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay. Results: IPC exerted significant cardioprotection and markedly improved myocardial glucose uptake 1 h after reperfusion (P<0.01) as evidenced by PET images and gamma-counter biodistribution assay in ischemia/reperfused rats. Meanwhile, myocardial translocation of glucose transporter 4 (GLUT4) to plasma membrane together with myocardial Akt and AMPK phosphorylation were significantly enhanced in preconditioned hearts. Intramyocardial injection of GLUT4 siRNA markedly decreased GLUT4 expression and blocked the cardioprotection of IPC as evidence by increased myocardial infarct size. Moreover, the PI3K inhibitor wortmannin significantly inhibited activation of Akt and AMPK, reduced GLUT4 translocation, glucose uptake and ultimately, depressed IPC-induced cardioprotection. Furthermore, IPC-afforded antiapoptotic effect was markedly blunted in STZ-treated diabetic rats. Exogenous insulin supplementation significantly improved glucose uptake via co-activation of myocardial AMPK and Akt and alleviated ischemia/reperfusion injury as evidenced by reduced myocardial apoptosis and infarction size in STZ-treated rats (P<0.05). Conclusions: The present study firstly examined the role of myocardial glucose metabolism during reperfusion in IPC using direct genetic modulation in vivo. Augmented glucose uptake via co-activation of myocardial AMPK and Akt in reperfused myocardium is essential to IPC-alleviated reperfusion injury. This intrinsic metabolic modulation and cardioprotective capacity are present in STZ-treated hearts and can be triggered by insulin. [ABSTRACT FROM AUTHOR]