Abstract
Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.
Highlights
Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure
We have reported that treatment of rat cardiac fibroblasts with adenosine triphosphate (ATP) downregulates angiotensin type 1 receptor (AT1R) through induction of inducible nitric oxide (NO) s ynthase12. P2Y2R mediates ATP-induced suppression of cardiomyocyte hypertrophy[10] and nutritional deficiency-induced cardiomyocyte a trophy11. P2Y6R, activated mainly by uracil diphosphate (UDP), changes the contractility of mouse cardiomyocytes[13]
We knocked down P2Y6R in neonatal rat cardiomyocytes (NRCMs) using two siRNAs (siP2Y6R #1 and #2), and examined cell damage and size after hypotonic stimulation, which is a model of in vitro pressure overload
Summary
Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overloadinduced heart failure in mice, P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis. P2Y6R is upregulated in pressure overloaded mouse hearts, and pharmacological inhibition of P 2Y6R by MRS2578 attenuates pressure overload-induced cardiac fibrosis[7] These findings indicate that P2Y6R in cardiovascular systems is a promising therapeutic target for cardiovascular dysfunction. It is not clear whether pressure overload-induced heart failure can be attenuated in P2Y6R-deficient mice. P 2Y6R deficiency did not affect doxorubicin (DOX)-induced heart failure; systemic deletion of P 2Y6R augments cardiac vulnerability to mechanical stress
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