NAMPT/SIRT1 Attenuate Ang II-Induced Vascular Remodeling and Vulnerability to Hypertension by Inhibiting the ROS/MAPK Pathway.

Lei Zhou,Enkhbat Bolor-Erdene,Sheng Zhang,Yunqing Mei,Lingwei Wang,Ding Tian,Karolina Szewczyk-Golec

doi:10.1155/2020/1974265

Abstract

Hypertension is characterized by endothelial dysfunction, vascular remodeling, and rearrangement of the extracellular matrix. Besides, the pathogenesis of hypertension is closely related to excess generation of reactive oxygen species (ROS). Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis that influences the activity of NAD-dependent enzymes, such as sirtuins, which possess NAD-dependent protein deacetylase activity and cleave NAD during the deacetylation cycle. Recently, NAMPT has been shown to play a crucial role in various diseases associated with oxidative stress. However, the function and regulation of NAMPT in hypertension have not been extensively explored. In the present study, we identified NAMPT as a crucial regulator of hypertension, because NAMPT expression was significantly downregulated in both patients with hypertension and experimental animals. NAMPT knockout (NAMPT+/-) mice exhibited a significantly higher blood pressure and ROS levels after stimulation with angiotensin II (Ang II) than wild-type mice, and the administration of recombinant human NAMPT (rhNAMPT) reversed this effect. In vivo, overexpression of NAMPT protected against angiotensin II- (Ang II-) induced hypertension by inhibiting ROS production via sirtuin 1 in mouse aortic endothelial cells (MAECs) and mouse aortic vascular smooth muscle cells (MOVAs). In turn, NAMPT alleviated the ROS-induced mitogen-activated protein kinase (MAPK) pathway. In conclusion, NAMPT might be a novel biomarker and a therapeutic target in hypertension.

Highlights

As an important and independent risk factor for cardiovascular disease (CVD), hypertension affects 30% of adults and has been the leading risk factor for heart attack and stroke [1]
Nicotinamide phosphoribosyltransferase (NAMPT) Expression Is Reduced in Tissues from Individuals with Hypertension, Mouse Aortic Vascular Smooth Muscle Cells (MOVAs), and Mouse Aortic Endothelial Cells (MAECs) Exposed to Angiotensin II (Ang II)
The rats were continually stimulated with Ang II through osmotic minipumps for 4 weeks, and fresh aortic wall tissues were collected; immunochemical staining and Western blotting revealed a significant reduction in Ang IIinduced hypertension in rats (Figures 1(b) and 1(d))

Summary

Introduction

As an important and independent risk factor for cardiovascular disease (CVD), hypertension affects 30% of adults and has been the leading risk factor for heart attack and stroke [1]. Angiotensin II (Ang II), the initial effector molecule of the renin-angiotensin system (RAS), has been shown to induce NAD(P)H oxidase (NOX) activity and increase local reactive oxygen species (ROS) production by binding to AT1R [2]. ROS-induced endothelial dysfunction appears to be the key early step in the development of hypertension [3]. The stimulation of vascular smooth muscle cell (VSMC) proliferation and rearrangement of extracellular matrix (ECM) formation are the major adaptive mechanisms involved in vascular alterations [4]. The ROSsensitive mitogen-activated protein kinase (MAPK) cascade is presumed to play a crucial role in endothelial cell (EC) dysfunction, the proliferation and migration of VSMCs, and formation of ECM through Ang II and ROS [5, 6]

Methods

Results

Conclusion