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Ramipril Protects the Endothelium From High Glucose-Induced Dysfunction Through CaMKKβ/AMPK and Heme oxygenase-1 Activation

Ramipril Protects the Endothelium From High Glucose-Induced Dysfunction Through CaMKKβ/AMPK and Heme oxygenase-1 Activation

Shiliu Tian, Xinfa Ge, Ke Wu, Huabing Yang, Yu Liu

J Pharmacol Exp Ther. 2014 Jul;350(1):5-13.

PMID: 24741076

Abstract:

This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKβ (Ca(2+)/calmodulin-dependent protein kinase kinase-β) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKβ/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKβ or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-β, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP108313117	Ramipril Related Compound A		108313-11-7	Price
CS31043020	Ramipril Related Compound C			Price

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