Abstract
Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y(6) receptor (P2Y(6)R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y(6)R prevents or promotes heart failure. We demonstrate that inhibition of P2Y(6)R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y(6)R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y(6)R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y(6)R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y(6)R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y(6)R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y(6)R exacerbates pressure overload-induced heart failure in mice, although P2Y(6)R in cardiomyocytes contributes to the progression of cardiac fibrosis.