Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms

► We demonstrate distinct cardiac gene regulation by p38α and p38β. ► p38α induces BNP transcription through AP-1 and p38β through GATA-4. ► p38β is the main regulator of the expression of hypertrophy-related genes. ► p38α regulates the expression of fibrosis-related genes. Persistent controversy underlies the functional roles of specific p38 MAPK isoforms in cardiac biology and regulation of hypertrophy-associated genes. Here we show that adenoviral gene transfer of p38β but not p38α increased B-type natriuretic peptide (BNP) mRNA levels in vitro as well as atrial natriuretic peptide mRNA levels both in vitro and in vivo. Overexpression of p38α, in turn, augmented the expression fibrosis-related genes connective tissue growth factor, basic fibroblast growth factor and matrix metalloproteinase-9 both in vitro and in vivo. p38β-induced BNP transcription was diminished by mutation of GATA-4 binding site, whereas overexpression of MKK6b, an upstream regulator of p38α and p38β, activated BNP transcription through both GATA-4 and AP-1. Overexpression of MKK3, upstream regulator of p38α, induced BNP transcription independently from AP-1 and GATA-4. These data provide new evidence for diversity in downstream targets and functional roles of p38 pathway kinases in regulation of hypertrophy-associated cardiac genes.