Loss of Mouse P2Y4 Nucleotide Receptor Protects against Myocardial Infarction through Endothelin-1 Downregulation

Abstract

Nucleotides are released in the heart under pathological conditions, but little is known about their contribution to cardiac inflammation. The present study defines the P2Y4 nucleotide receptor, expressed on cardiac microvascular endothelial cells and involved in postnatal heart development, as an important regulator of the inflammatory response to cardiac ischemia. P2Y4-null mice displayed smaller infarcts in the left descending artery ligation model, as well as reduced neutrophil infiltration and fibrosis. Gene profiling identified inter alia endothelin-1 (ET-1) as one of the target genes of P2Y4 in ischemic heart. The reduced level of ET-1 was correlated with reduction of microvascular hyperpermeability, neutrophil infiltration, and endothelial adhesion molecule expression, and it could be explained by the decreased number of endothelial cells in P2Y4-null mice. Expression analysis of metalloproteinases and their tissue inhibitors in ischemic heart revealed reduced expression of matrix metalloproteinase (MMP)-9, reported to be potentially regulated by ET-1, and MMP-8, considered as neutrophil collagenase, as well as reduction of tissue inhibitor of MMP-1 and tissue inhibitor of MMP-4 in P2Y4-null mice. Reduction of cardiac permeability and neutrophil infiltration was also observed in P2Y4-null mice in LPS-induced inflammation model. Protection against infarction resulting from loss of P2Y4 brings new therapeutic perspectives for cardiac ischemia and remodeling.

Ovariectomy uncovers purinergic receptor activation of endothelin-dependent natriuresis

“…Despite their overlapping spheres of influence, information on potential interplay between renal P2 and ET receptors is rare. The interaction between ET-1 and P2 signaling systems has been also demonstrated in extrarenal tissues (1,4,31,35). Our current findings demonstrate that activation of medullary P2 receptors promotes ET-1-dependent natriuresis in OVX rats, similar to male rats (23).…”

Loss of Mouse P2Y6 Nucleotide Receptor Is Associated with Physiological Macrocardia and Amplified Pathological Cardiac Hypertrophy

“…Cardiac Echography Experiments-Cardiac echography experiments were assessed as previously described (5). Briefly, transthoracic echography was performed on anesthetized mice (1% isoflurane), using a Vevo 2100 system equipped with a 40 MHz transducer (Visualsonics, Toronto, Canada).…”

“…Another UTP receptor, P2Y 4 , plays an important role in the heart: P2Y 4 knock-out (KO) mice display reduced cardiac angiogenesis and cardiac postnatal development (3), as well as lower exercise capacity and reduced exercise-induced cardiac hypertrophy (4). More recently, it has been shown that P2Y 4 KO mice display lower infarct size and reduced cardiac inflammation and fibrosis in a model of ligation of the left anterior descending artery (5). The study of the role of P2Y 6 UDP receptor in the heart has also been initiated.…”

“…We analyzed the role of this UDP receptor in physiological and pathological cardiac hypertrophy using P2Y 6 -null mice. We used the model of intraperitoneal injection of isoproterenol (ISO), 5 a non-selective agonist of ␤-adrenergic receptors, which is a model frequently used to induce pathological cardiac hypertrophy (12)(13)(14).…”

Preliminary in vitro analysis of mechanism of cardiac microvascular endothelial barrier function

“…The increase in oxygen free radicals in heart failure patients leads to EC dysfunction, which causes further deterioration of cardiac function, forming a vicious cycle (Horckmans et al, 2015). Vascular ECs also interact with platelets, white blood cells, and blood vessels and can control the growth of blood vessels.…”