Progression of Atherosclerosis is Slowed in Mice via Targeting Senescent Cells

We reported that plasma levels of angptl2 are elevated in patients with cardiovascular diseases (CVD), were associated with endothelial dysfunction, and were predictive of major cardiac adverse events and death. Recently, we reported a strong relationship between arterial expression of p21, a cell cycle inhibitor overexpressed in senescent cells and maintaining growth arrest, and circulating levels of angptl2 in atherosclerotic patients. Senescent EC are activated and promote aggregation of leukocytes, the initiating step of atherogenesis. We therefore hypothesized that down-regulation of vascular angptl2, preferentially in the endothelium of severely dyslipidemic ATX mice would promote endothelial repair and slow atherogenesis. Here, we report that knockdown of vascular angptl2 by a shRNA (shAngptl2), delivered to the vascular cells via a single injection of an AAV1, slowed atheroma progression in ATX mice. Knockdown of angptl2 was associated with a rapid reduction in the expression of EC senescence-associated p21 accompanied by the increase in Bax/Bcl2 ratio as a marker of apoptosis; subsequently, this was associated with endothelial repair as evidenced by the incorporation of endothelial progenitor CD34+ cells. In addition to our pre-clinical results, we show that vascular ANGPTL2 gene expression is correlated with p21 expression and inflammatory cytokines in the internal mammary artery isolated from severely atherosclerotic patients undergoing a coronary artery by...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs