Stage-specific differential activation of mitogen-activated protein kinases in hypertrophied and failing rat hearts

Mitogen-activated protein kinases (MAPKs) are involved in the early develop ment of cardiac hypertrophy, but their roles in chronic left ventricular hy pertrophy (LVH) are unclear, We studied the angiotensin (Ang) II-induced ca rdiac MAPK activation of the hypertensive Dahl salt-sensitive (DS) rats in the subacute developing LVH stage, the chronic compensated LVH stage, and t he congestive heart failure (CHF) stage, In the isolated, coronary-perfused heart preparation, Ang II infusion (1 x 10(-6) mol/l) activated extracellu lar signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38-MA PK in the LV myocardium. No substantial differences were observed in the An g II-induced ERK activation between the normotensive control DS rats and th e hypertensive DS rats in either stage, In contrast, the Ang II-induced act ivation of JNK and p38-MAPK was augmented in the subacute LVH stage of the hypertensive DS rats, but then progressively attenuated in the chronic LVH and CHF stages, Chronic treatment with an angiotensin converting enzyme inh ibitor, temocapril (20 mg/kg/day), ameliorated the responsiveness of the JN K/p38-MAPK activation, suggesting that the decreased JNK/p38-MAPK activatio n is a consequence of negative feedback; regulation for the activated cardi ac renin-angiotensin system in chronic LVH and CHF. Thus, the Ang II-induce d activation of multiple cardiac MAPK pathways are differentially regulated , depending on the stages of chronic hypertrophic process. The JNK and p38- MAPK activation may be involved in the early development of adaptive LVH. H owever, the responsiveness of the cardiac JNK/p38-MAPK pathways progressive ly decreased in chronic LVH and CHF under the chronic activation of tissue renin-angiotensin system, (C) 2001 Academic Press.