Modulation of P2Y₆R expression exacerbates pressure overload-induced cardiac remodeling in mice.

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.

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