Protective effects of intermedin/adrenomedullin-2 in a cellular model of human pulmonary arterial hypertension

Abstract

Proliferation of pulmonary fibroblasts (PF) and distal migration of smooth muscle cells (PSM) are hallmarks of pulmonary arterial hypertension (PAH). Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the Calcitonin Gene-Related Peptide (CGRP)/Adrenomedullin (AM) superfamily. These peptides act via Calcitonin-Like Receptors (CLR) combined with one of three Receptor activity-modifying proteins (RAMPs). IMD/AM2 is a potent pulmonary vasodilator in animal studies. The aim was to describe expression of IMD/AM2, AM and receptor components in human pulmonary vascular cells and to elucidate effects of IMD/AM2 on human PSM migration and PF proliferation. Gene expression was detected by immunofluorescence, immunoblotting and qRT-PCR. Normotension and hypertension were simulated by applying pulsatile mechanical stretch (Flexcell® apparatus). Viable cell numbers were determined by dye exclusion. PSM chemotaxis was measured via Dunn chamber. IMD/AM2 protein was co-expressed with AM and their receptor components in pulmonary artery and microvascular endothelial (PAEC, PMVEC) and non-endothelial cells (PF, PSM), and localised to vesicles. IMD/AM2 was secreted under basal conditions, most abundantly from PF and PMVEC. Secretion from PF and PSM was enhanced by stretch. IMD/AM2 mRNA expression increased in response to hypertensive stretch of PSM. IMD/AM2 inhibited PDGF (10 −7 M)-mediated PSM migration maximally at 3 × 10-10 M and PF proliferation maximally at 3 × 10-9 M. Angiotensin II (5 × 10-8 M), normotensive and hypertensive stretch augmented PF proliferation. IMD/AM2 (10-9 M) abolished the proliferative effects of Angiotensin II and normotensive stretch and attenuated the proliferative effect of hypertensive stretch alone and combined with angiotensin II. These findings indicate an important counter-regulatory role for IMD/AM2 in PAH.

Pulsatility protects the endothelial glycocalyx during extracorporeal membrane oxygenation

“…In vitro flow shear stress experiments were conducted using the Flexcell apparatus (Flexcell™ Inc., McKee-sport, PA, USA), as described elsewhere. [24][25][26] PMVECs were seeded on 6-well Flexcell plates and were incubated for 2 days. Seeded PMVECs (1 × 10 5 cells per well) were deprived of FBS and were exposed to fluid (PBS) shear stresses (flow rate: 2 ml/min, viscosity: 0.7 mPa/s, absence of blood proteins, at 37°C and 5% CO 2 ) at a frequency of 1 Hz.…”

Intermedin Reduces Oxidative Stress and Apoptosis in Ventilator-Induced Lung Injury via JAK2/STAT3

“…The IMD gene is located on human chromosome 22q13.33, and the encoded polypeptide chain is composed of 148 amino acids ( Zhang and Xu, 2018 ). The N-terminal of IMD is an intramolecular ring composed of six amino acids and an α-helical structure ( Takei et al, 2004 ; Holmes et al, 2020 ; Sohn et al, 2020 ). Human IMD sequences are 60% similar to fish and 87% similar to rodents ( Roh et al, 2004 ).…”

“…Intermedin (IMD) is a novel polypeptide belonging to the calcitonin superfamily. IMD is widely expressed throughout the body, and its sequence is highly conserved among different species ( Hong et al, 2012 ; Holmes et al, 2020 ; Sohn et al, 2020 ). IMD is a homeostasis regulating peptide involved in many life activities, such as glucose and lipid metabolism, inhibition of inflammation, maintaining cardiovascular system stability, tissue repair, and other aspects ( Wang et al, 2020 ; Ren et al, 2021 ).…”

Adrenomedullin is a biological marker of heart failure: review of modern literature Amina M. Alieva*1, Natalia

“…Помимо вазодилатации ADM, по-видимому, играет важную роль в ингибировании апоптоза кардиомиоцитов и клеток эндотелия [11]. Другими биологическими свойствами гормона являются диуретический и натрийуретический, положительный инотропный эффект, индукция ангиогенеза, ингибирование образования альдостерона, бактерицидное действие, иммуномодулирующий эффект и антиоксидантная активность [14].…”