Gene deletion of P2Y₄ receptor lowers exercise capacity and reduces myocardial hypertrophy with swimming exercise

Abstract

Nucleotides released within the heart under pathological conditions can be involved in cardioprotection or cardiac fibrosis through the activation purinergic P2Y(2) and P2Y(6) receptors, respectively. We previously demonstrated that adult P2Y(4)-null mice display a microcardia phenotype related to a cardiac angiogenic defect. To evaluate the functional consequences of this defect, we performed here a combination of cardiac monitoring and exercise tests. We investigated the exercise capacity of P2Y(4) wild-type and P2Y(4)-null mice in forced swimming and running tests. Analysis of their stress, locomotion, and resignation was realized in open field, black and white box, and tail suspension experiments. Exercise-induced cardiac hypertrophy was evaluated after repeated and prolonged exercise in P2Y(4) wild-type and P2Y(4)-null hearts. We showed that P2Y(4)-null mice have a lower exercise capacity in both swimming and treadmill tests. This was not related to decreased motivation or increased stress, since open field, white and black box, and mouse tail suspension tests gave comparable results in P2Y(4) wild-type and P2Y(4)-null mice. Heart rate and blood pressure rose normally in P2Y(4)-null swimming mice equipped with a telemetric implant. On the contrary, we observed a delayed recovery of postexercise blood pressure after exercise in P2Y(4)-null mice. The heart rate increment in response to catecholamines was also similar in P2Y(4) wild-type and P2Y(4)-null implanted mice, which is consistent with a similar level of cardiac β-receptor expression. Interestingly, the heart of P2Y(4)-null mice displayed a reduced sympathetic innervation associated with a decreased norepinephrine level. We also demonstrated that exercise-induced cardiac hypertrophy was lower in P2Y(4)-null mice after repeated and prolonged exercise. This was associated with a lower increase in cardiomyocyte size and microvessel density. In conclusion, besides its role in cardiac development, P2Y(4) receptor could constitute an important regulator of acute and chronic response to exercise.

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

“…P2Y 4 , described as a UTP receptor (16), displays a very restricted tissue distribution including heart and lung, and its physiological role has been poorly investigated. We have previously demonstrated that adult P2Y 4 -null mice display a microcardia phenotype related to a cardiac angiogenic defect (23) and a reduced exercise tolerance (24). The present study identifies a protection against myocardial infarction in P2Y 4 -null mice.…”

“…P2Y 4 -null mice have been generated in our laboratory (22) and we demonstrated P2Y 4 (23). We showed recently that this receptor is involved in postnatal heart development (23), as well as in exercise tolerance and exercise-induced cardiac hypertrophy (24).…”

Cardiac purinergic signalling in health and disease

“…Overexpression of human P2X4R in ventricular myocytes of a transgenic mouse increased basal cardiac contractility without cardiac hypertrophy or failure [274] and activation with a P2X4R agonist had beneficial effects [483]. Deletion of the P2Y4R gene in mice lowered exercise capacity and reduced myocardial hypertrophy [737].…”

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

“…Cardioprotective effect of UTP has been previously described: treatment with UTP prior to myocardial infarction leads to reduced ischemic damage through P2Y 2 receptor activation (1,2). 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).…”

“…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.…”