Protective Role of Endogenous Kallistatin in Vascular Injury and Senescence by Inhibiting Oxidative Stress and Inflammation

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.

Endothelial progenitor cells overexpressed with omentin-1 enhance the inhibition of neointimal hyperplasia via anti-inflammation

“…One of them is that the number of EPCs has decreased signi cantly when long-term exposure to the condition of hyperlipidemia and hyperglycemia [21]. The other is that EPCs therapy is compromised by the CD34-positive cells differentiation into smooth muscle progenitor cells (SMPC) and decreased function of EPCs mainly due to in ammatory cascade in the harsh environment, which in turn inhibits vascular repair and reendothelialization [22][23][24][25]. Thus, to circumvent these problems, many approaches have been attempted to enhance EPCs functions.…”

Proteomics-Based Detection of Immune Dysfunction in an Elite Adventure Athlete Trekking Across the Antarctica

“…Kallistatin is a unique serine protease inhibitor (serpin family A member 4) and was one of several serpins elevated during the Antarctica trek and five weeks of recovery. Kallistatin has many roles including suppression of cytokine signaling expression in macrophages [37,38]. Kallistatin antagonizes tumor necrosis factor (TNF)-α induced inflammation, oxidative stress, and apoptosis while enhancing bacterial clearance and exerting anti-inflammatory effects.…”

“…Kallistatin antagonizes tumor necrosis factor (TNF)-α induced inflammation, oxidative stress, and apoptosis while enhancing bacterial clearance and exerting anti-inflammatory effects. The elevation of kallistatin during the Antarctica trek and recovery appears to represent one attempt by the immune system to restore homeostasis [38].…”

Comprehensive analysis of angiogenesis-related genes and pathways in early diabetic retinopathy

“…Increasing evidence suggests that angiogenesis is associated with various biological processes and pathways in DR, such as the mitogen-activated protein kinase signaling pathway [ 8 ] and the tumour necrosis factor signaling pathway [ 9 ]. Animal experiments indicated that anti-angiogenic therapy in early DR may have a positive effect on the prognosis [ 10 , 11 ].…”