Endothelial permeability in vitro and in vivo: Protective actions of ANP and omapatrilat in experimental atherosclerosis

Abstract

Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I 125 albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system.

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis

“…Our current study showed the crucial role of MAGI1 PTMs in simultaneously regulating EC activation and ER stress-mediated apoptosis and poses MAGI1 as an attractive therapeutic target to inhibit atherosclerosis and subsequent adverse cardiovascular events. There were no additive effects of complete depletion (homozygous) or partial inhibition (heterozygous) of MAGI1 on d-flow-induced atherosclerotic plaque formation, probably due to increased EC permeability owed to complete MAGI1 deletion, because the increase of EC permeability may enhance the atherosclerosis formation (41). We plan to investigate the role of MAGI1 and its PTMs in regulating EC permeability in future studies.…”

Aging‐related carcinoembryonic antigen‐related cell adhesion molecule 1 signaling promotes vascular dysfunction

“…Progressive age is characterized by ED, which includes enhanced endothelial permeability (Bömmel et al., ; Ichiki et al., ; Phinikaridou et al., ; Rodríguez‐Mañas et al., ). Therefore, we conducted experiments to evaluate endothelial permeability in WT and Cc1 −/− mice in situ.…”

Regulatory mechanisms, prophylaxis and treatment of vascular leakage following severe trauma and shock

“…Interestingly, ANP can be rapidly degraded by neprilysin (NEP), which can be suppressed by omapatrilat , thus reducing the leakage area of the arteries. Ichiki et al (2013) found that such a dual inhibitory effect on NEP might be related to the ANP/cGMP pathway [77]. Chen et al [78] found that ANP can impede the phosphorylation of the MLC gene by inhibiting the GC/cGMP and the TRPC6 pathways.…”