Abstract
Kallistatin was identified in human plasma as a tissue kallikrein-binding protein and a serine proteinase inhibitor. Kallistatin exerts pleiotropic effects on angiogenesis, oxidative stress, inflammation, apoptosis, fibrosis, and tumor growth. Kallistatin levels are markedly reduced in patients with coronary artery disease, sepsis, diabetic retinopathy, inflammatory bowel disease, pneumonia, and cancer. Moreover, plasma kallistatin levels are positively associated with leukocyte telomere length in young African Americans, indicating the involvement of kallistatin in aging. In addition, kallistatin treatment promotes vascular repair by increasing the migration and function of endothelial progenitor cells (EPCs). Kallistatin via its heparin-binding site antagonizes TNF-α-induced senescence and superoxide formation, while kallistatin's active site is essential for inhibiting miR-34a synthesis, thus elevating sirtuin 1 (SIRT1)/eNOS synthesis in EPCs. Kallistatin inhibits oxidative stress-induced cellular senescence by upregulating Let-7g synthesis, leading to modulate Let-7g-mediated miR-34a-SIRT1-eNOS signaling pathway in human endothelial cells. Exogenous kallistatin administration attenuates vascular injury and senescence in association with increased SIRT1 and eNOS levels and reduced miR-34a synthesis and NADPH oxidase activity, as well as TNF-α and ICAM-1 expression in the aortas of streptozotocin- (STZ-) induced diabetic mice. Conversely, endothelial-specific depletion of kallistatin aggravates vascular senescence, oxidative stress, and inflammation, with further reduction of Let-7g, SIRT1, and eNOS and elevation of miR-34a in mouse lung endothelial cells. Furthermore, systemic depletion of kallistatin exacerbates aortic injury, senescence, NADPH oxidase activity, and inflammatory gene expression in STZ-induced diabetic mice. These findings indicate that endogenous kallistatin displays a novel role in protection against vascular injury and senescence by inhibiting oxidative stress and inflammation.
Highlights
Aging is a major risk factor for the development of many diseases, including cardiovascular disease, stroke, and cancer [1,2,3]
Endothelial aging is associated with increased oxidative stress and inflammation and decreased endothelial nitric oxide synthase activity and nitric oxide (NO) production [4, 5]
Levels of the antioxidant proteins sirtuin 1 (SIRT1) and endothelial nitric oxide synthase (eNOS) were significantly reduced in the aorta of KS−/− mice with STZinduced diabetes (Figure 3(e)), in contrast to the stimulatory effect of kallistatin administration on SIRT1 and eNOS expression [56]
Summary
Aging is a major risk factor for the development of many diseases, including cardiovascular disease, stroke, and cancer [1,2,3]. Oxidative stress impairs the mobility and function of endothelial progenitor cells (EPCs) and enhances cellular senescence [6]. Kallistatin exerts multifactorial activities, including vasodilation and inhibition of oxidative stress, inflammation, fibrosis, and apoptosis, primarily by increasing eNOS levels and NO formation [17,18,19,20,21,22]. Kallistatin administration increases circulating EPC number and reduces aortic oxidative stress, whereas kallistatin depletion augments endothelial cell loss, diminishes circulating EPC levels, and exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling in hypertensive rats [23, 24]. Telomere length is critically related to vascular cell senescence, Oxidative Medicine and Cellular Longevity. Kallistatin via NO formation may protect against vascular injury, senescence, and aging through its antioxidant and anti-inflammatory actions
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