Sirt5 in mediating endothelial and vascular dysfunction: a novel target in aging-related vascular diseases

Abstract Background Growing aging population worldwide brings the prevalence of cardiovascular diseases (CVDs) into a significant public health concern. Understanding the underlying mechanisms of aging-associated CVDs is critical for developing targeted prevention and treatment approaches. It is rarely known about the roles of the lifespan-regulating member SIRT5 in cardiovascular function. Purpose We aimed to study the roles of Sirt5 on vascular function during aging, decipher the underlying mechanisms, and to explore its potential as a therapeutic target through in vivo and in vitro studies. Methods The aortic function of aged wild type (WT) mice and Sirt5-overexpressing transgenic mice (Sirt5/Tg) were studied with myograph system, and the structural assessment with histological staining. Protein level of SIRT5 during aging were studied in aorta from young and aged WT mice, and in human aortic endothelial cells (HAECs) before (passage 6-8) and after senescence (passages 13-15) in western blotting. Regulatory effects of Sirt5 in HAECs were studied by knock-down experiments using siRNA, followed by assessment of endothelial nitric oxide synthase (eNOS)-related pathway. The therapeutic potential of Sirt5 inhibition was explored in aorta from aged mice and in HAECs using specific Sirt5 inhibitors. Results . Sirt5/Tg mice displayed injured aortic function by showing a reduced relaxation to acetylcholine, and thickened adventitia collagen layer compared to the wildtype mice. Sirt5 level was increased significantly in both aorta from aged mice and senescent HAECs. Inhibition of Sirt5 with specific inhibitors and knockdown of Sirt5 with siRNA induced expression of total and phosphorated (S1177) eNOS in HAECs. Upregulated AMPK level in senescent HAECs were decreased by the knockdown of SIRT5. Further, incubation of Sirt5 inhibitor with aorta from aged mice improved endothelial function in the vascular functional assessment in myograph system, indicating the therapeutic potential in aging associated vascular diseases by targeting at Sirt5. Conclusion Vascular Sirt5 expression increases with age and contributes to aging-related endothelial dysfunction by downregulating the eNOS pathway. Thus, Sirt5 inhibition may represent a novel therapeutic approach to maintain vascular function during aging.