Knockdown Of Natriuretic Peptide Receptor- A Enhances Receptor-C Expression And Signaling In Vascular Smooth Muscle Cells (Vsmc)

Natriuretic peptide receptor‐A (NPR‐A) knockout mice were reported to exhibit an increased blood pressure which may also be attributed to the upregulation of NPR‐C and associated signaling, however, the interaction between the two receptors was not investigated. In the present study, we investigated the effect of knockdown of NPR‐A using NPR‐A antisense (AS) on the expression of NPR‐C and adenylyl cyclase (AC) signaling in VSMC. Treatment of VSMC with NPR‐A AS decreased the expression of NPR‐A and enhanced the expression of NPR‐C but not of AT1 and M2 receptor. In addition, siRNA‐NPR‐A also upregulated NPR‐C. The re‐expression of NPR‐A in AS‐treated cells reversed the enhanced expression of NPR‐C to control levels. In addition, the receptor‐mediated inhibitions of AC activity and Giα expression were enhanced in AS‐treated cells, whereas NPR‐A‐mediated cGMP formation was significantly reduced. Pertussis toxin treatment attenuated AS‐induced enhanced inhibitions of AC to control levels. Furthermore, the enhanced levels of NPR‐C and Giα proteins were reversed to control levels by 8Br‐cGMP and PD98059. In addition, 8Br‐cGMP also attenuated AS‐induced enhanced ERK1/2 phosphorylation to control levels. These results demonstrate that knockdown of NPR‐A upregulates the expression of NPR‐C, Giα proteins and NPR‐C‐linked AC signaling and suggest a cross‐talk between NPR‐A and NPR‐C(Supported by CIHR).