The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy

Stress-induced mitogen-activated protein kinase (MAP) p38 is activated in v arious forms of heart failure, yet its effects on the intact heart remain t o be established. Targeted activation of p38 MAP kinase in ventricular myoc ytes was achieved in vivo by using a gene-switch transgenic strategy with a ctivated mutants of upstream kinases MKK3bE and MKK6bE. Transgene expressio n resulted in significant induction of p38 kinase activity and premature de ath at 7-9 weeks. Both groups of transgenic hearts exhibited marked interst itial fibrosis and expression of fetal marker genes characteristic of cardi ac failure, but no significant hypertrophy at the organ level. Echocardiogr aphic and pressure-volume analyses revealed a similar extent of systolic co ntractile depression and restrictive diastolic abnormalities related to mar kedly increased passive chamber stiffness. However, MKK3bE-expressing heart s had increased end-systolic chamber volumes and a thinned ventricular wall , associated with heterogeneous myocyte atrophy, whereas MKK6bE hearts had reduced end-diastolic ventricular cavity size, a modest increase in myocyte size, and no significant myocyte atrophy. These data provide in vivo evide nce for a negative inotropic and restrictive diastolic e ect from p38 MAP k inase activation in ventricular myocytes and reveal specific roles of p38 p athway in the development of ventricular end-systolic remodeling.