Age‐dependent changes in P2Y receptors in the hearts of P2Y2 knockout mice

Genetic ablation in mice of the nucleotide receptor P2Y2 leads to salt‐resistant hypertension and changes in several organ systems. In the current study we employed this animal model to investigate age‐dependent changes in cardiac P2Y receptor expression. Using quantitative PCR, we determined the expression level of seven P2Y receptor subtypes, P2Y1, 2, 4, 6, 12, 13 and 14 in hearts of wild‐type (WT) and P2Y2 knockout (KO) mice at age of 4, 12 and 18 months. Hearts of WT mice have both P2Y1 and P2Y2 as the major receptor P2Y subtypes, with lower levels of RNA expression for P2Y6 and P2Y14. All four P2Y subtypes exhibit striking increases in expression in 18 month‐old mice whereas the other three P2Y subtypes have low expression levels and display no significant age‐dependent changes. In contrast, KO mice have elevated expression of all six of the other P2Y subtypes and demonstrate similar age‐dependent patterns of change as do WT mice, with increases in P2Y1, P2Y6 and P2Y14 in the 18‐month old group. These results demonstrate that P2Y2 receptors are an important subtype in the heart, such that their absence results in compensatory expression of other P2Y subtypes. Since P2Y2 KO mice are hypertensive, the observed changes in other cardiac P2Y receptors may represent adaptations to increase in blood pressure as well as to the absence of P2Y2 receptors. (Grant support from NIH, UCSD SIRA and the Ellison Medical Foundation)