AT2R agonist NP‐6A4 mitigates aortic stiffness and proteolytic activity in mouse model of aneurysm

Neekun Sharma,Anthony M Belenchia,Lakshmi Pulakat,Ryan Toedebusch,Chetan P Hans

doi:10.1111/jcmm.15342

Abstract

Clinical and experimental studies show that angiotensin II (AngII) promotes vascular pathology via activation of AngII type 1 receptors (AT1Rs). We recently reported that NP‐6A4, a selective peptide agonist for AngII type 2 receptor (AT2R), exerts protective effects on human vascular cells subjected to serum starvation or doxorubicin exposure. In this study, we investigated whether NP‐6A4–induced AT2R activation could mitigate AngII‐induced abdominal aortic aneurism (AAA) using AngII‐treated Apoe−/− mice. Male Apoe−/− mice were infused with AngII (1 µg/kg/min) by implanting osmotic pumps subcutaneously for 28 days. A subset of mice was pre‐treated subcutaneously with NP‐6A4 (2.5 mg/kg/day) or vehicle for 14 days prior to AngII, and treatments were continued for 28 days. NP‐6A4 significantly reduced aortic stiffness of the abdominal aorta induced by AngII as determined by ultrasound functional analyses and histochemical analyses. NP‐6A4 also increased nitric oxide bioavailability in aortic tissues and suppressed AngII‐induced increases in monocyte chemotactic protein‐1, osteopontin and proteolytic activity of the aorta. However, NP‐6A4 did not affect maximal intraluminal aortic diameter or AAA incidences significantly. These data suggest that the effects of AT2R agonist on vascular pathologies are selective, affecting the aortic stiffness and proteolytic activity without affecting the size of AAA.

Highlights

Hyperactive angiotensin II (AngII) type 1 receptors (AT1Rs) induces inflammatory signalling resulting in oxidative stress, and pathological sequelae of vasculopathies that cause hypertension, and micro- and macrovascular damage including abdominal aortic aneurysm (AAA).[3,4]
AngII binds to both AT1R and AngII type 2 receptor (AT2R) in the vascular cells, the AngII-AT1R–induced inflammation overrides any protection induced by activation of AT2R by AngII in these models
We investigated whether vascular protective effects of NP-6A4-AT2R signalling on vasculopathies induced in male Apoe-/- mice via AngII (1 μg/kg/day) infusion

Summary

| INTRODUCTION

Cardiovascular diseases are the leading cause of death worldwide. Decades of research has established that the components of renin-angiotensin system (RAS) play a central role in maintaining cardiovascular physiology, including arterial compliance and regulation of blood pressure.[1,2] overactivation of RAS caused by metabolic imbalances such as obesity, hyperlipidaemia and diabetes, or infection results in increased presence of angiotensin II (AngII) and up-regulation of AngII type 1 receptor (AT1R). We have shown that NP-6A4 protects mouse HL-1 cardiomyocytes and human coronary artery vSMCs from acute nutrient deficiency.[13] These protective effects of AT2R stimulation have been well supported by other evidence for maintaining vascular integrity of the aorta.[14,15]. In a mouse model, AT2R deficiency had no effects on AngII-induced AAA and atherosclerosis.[16] These conflicting reports warrant further studies to confirm the roles of AT2R stimulation in the settings of AngII-induced aortic pathologies. Our results show that NP-6A4–induced AT2R signalling attenuates AngII-induced aortic stiffness as a primary outcome This protective effect involved increase in the bioavailability of NO in ECs and suppression of osteopontin and matrix metalloproteases (Mmps) in vSMCs. AngII-induced development of AAA as determined by maximal aortic diameter or increase in blood pressure was not suppressed by AT2R activation

| MATERIALS AND METHODS

Findings

| DISCUSSION