HIF-1α Signaling Activation by Post-Ischemia Treatment with Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury

Abstract

In this study, we evaluated the effect of astragaloside IV (Ast IV) post-ischemia treatment on myocardial ischemia-reperfusion (IR) injury (IRI). We also examined whether hypoxia inducible factor-1α (HIF-1α) and its downstream gene-inducible nitric oxide (NO) synthase (iNOS) play roles in the cardioprotective effect of Ast IV. Cultured cardiomyocytes and perfused isolated rat hearts were exposed to Ast IV during reperfusion in the presence or absence of the HIF-1α inhibitor 2-methoxyestradiol (2-MeOE2). The post-ischemia treatment with Ast IV protected cardiomyocytes from the apoptosis and death induced by simulated IRI (SIRI). Additionally, in cardiomyocytes, 2-MeOE2 and HIF-1α siRNA treatment each not only abolished the anti-apoptotic effect of post-ischemia treatment with Ast IV but also reversed the upregulation of HIF-1α and iNOS expression. Furthermore, after treatment with Ast IV, post-ischemic cardiac functional recovery and lactate dehydrogenase (LDH) release in the coronary flow (CF) were improved, and the myocardial infarct size was decreased. Moreover, the number of apoptotic cells was reduced, and the upregulation of the anti-apoptotic protein Bcl2 and downregulation of the pro-apoptotic protein Caspase3 were reversed. 2-MeOE2 reversed these effects of Ast IV on IR-injured hearts. These results suggest that post-ischemia treatment with Ast IV can attenuate IRI by upregulating HIF-1α expression, which transmits a survival signal to the myocardium.

Research review on the pharmacological effects of astragalosideIV

“…HIF‐1α, as the first response to ischemia in cellular level, is closely associated with a great deal of signaling pathway, such as HIF‐1α/iNOS and PI3K/Akt/HIF‐1α . Treatment with AS‐IV (50 μ m , 4 h) during the postischemia period also obviously increased the expression of HIF‐1α, iNOS, and Bcl‐2 and reduced the caspase‐3 expression and LDH release in IRI cardiomyocytes and isolated heart . Under the hypoxia condition, AS‐IV (25–50 μg/mL/31.8–63.6 μ m ) demonstrated the potent protective effect of cardiomyocytes via upregulating the expression and the activity of SOD‐1 and inhibiting the ROS and MDA under the physiological and hypoxic status in the cytoplasm .…”

Monocyte Chemoattractant Protein‐Induced Protein 1 Targets Hypoxia‐Inducible Factor 1α to Protect Against Hepatic Ischemia/Reperfusion Injury

“…We identified HIF‐1α as a partner that mediates MCPIP1 function in hepatic I/R injury. HIF‐1α is known to be a protective factor in human I/R injury and in multiple organ I/R injury models . For instance, a meta‐analysis demonstrated that HIF‐1α attenuated liver I/R injury .…”

“…HIF‐1α activation has been documented in multiple pathological conditions through different mechanisms . Particularly, HIF‐1α is a protective factor in hepatic I/R injury, and pharmacological stabilization of HIF‐1α protects against myocardial I/R injury . Interestingly, HIF‐1α is stabilized by MCPIP1 .…”

Endothelin Receptor Down-Regulation Mediated Ligand Regulation Mechanisms Protect Against Cellular Hypoxia Injury in Rat Vascular Endothelial Cells

“…Activated HIF-1 participates in cellular survival and apoptosis, as well as biological effects such as drug resistance. Overproduction of HIF-1 increases local inflammation and aggravates IR injury [23]. Interferon-γ (IFN-γ) is a secretive factor with the ability to induce macrophage iNOS production, the overproduction of which is important in pathological processes including inflammation and acute rejection [24].…”