Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: Potential roles for protein kinase C and mitogen-activated protein kinase

In cardiac myocytes, B-type natriuretic peptide (BNP) expression is induced with the rapid kinetics of a primary response gene. Like many other primary response gene transcripts, the BNP mRNA possesses destabilizing elements and is believed to be short-lived. The rapid induction of a short-lived transcript could be achieved partly by agonist-mediated increases in mRNA t(1/2). Accordingly, the present study was undertaken to evaluate whether the alpha(1)-adrenergic receptor agonist, phenylephrine (PE), a known inducer of BNP expression, could stabilize the BNP mRNA and, if so, what signaling pathways might be involved. in primary myocardial cells treated with a transcription inhibitor, the t(1/2) of the BNP mRNA was found to be about 1 h in the absence of RE; however, in the presence of PE, the t(1/2) increased to 5 h. It was shown that neither the calmodulin kinase inhibitor, KN-62, nor the protein tyrosine kinase inhibitor, tyrphostin, blocked RE-mediated stabilization of the BNP mRNA. However, either the protein kinase C (PKC) inhibitor, Or 109203X, or the mitogen-activated protein kinase kinase (MAPKK) inhibitor, PD 098059, effected some blockade of the stabilizing effects of RE. While maximal doses of PD 098059 nearly completely blocked PE-activated MARK, stabilization was only partially inhibited. Moreover, maximal doses of Or 109203X, which only partially blocked RE-activated MARK, nearly completely inhibited stabilization. Thus, while MAPK appears to be required for maximal agonist-mediated stabilization, PKC seems to play a dominant role, participating through both MAPK-dependent and -independent pathways. These results establish roles for both the PKC and families in alpha(1)-adrenergic receptor-mediated stabilization of the BNP mRNA, suggesting that the rapid induction of BNP expression might be due, in part, to this agonist-mediated increase in mRNA t(1/2).