Losartan decreases p42/44 MAPK signaling and preserves LZ+ MYPT1 expression.
Heart failure is associated with impairment in nitric oxide (NO) mediated vasodilatation, which has been demonstrated to result from a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. Further, captopril preserves normal LZ+ MYPT1 expression, the sensitivity to cGMP-mediated vasodilatation and modulates the expression of genes in the p42/44 MAPK and p38 MAPK signaling cascades. This study tests whether angiotensin receptor blockade (ARB) with losartan decreases p42/44 MAPK or p38 MAPK signaling and preserves LZ+ MYPT1 expression in a rat infarct model of heart failure. In aortic smooth muscle, p42/44 MAPK activation increases and LZ+ MYPT1 expression falls after LAD ligation. Losartan treatment decreases the activation of p42/44 MAPK to the uninfarcted control level and preserves normal LZ+ MYPT1 expression. The expression and activation of p38 MAPK, however, is low and does not change following LAD ligation or with losartan therapy. These data suggest that either reducing or blocking the effects of circulating angiotensin II, both decreases the activation of the p42/44 MAPK signaling cascade and preserves LZ+ MYPT1 expression. Thus, the ability of ACE-inhibitors and ARBs to modulate the vascular phenotype, to preserve normal flow mediated vasodilatation may explain the beneficial effects of these drugs compared to other forms of afterload reduction in the treatment of heart failure.
Division of Cardiovascular Diseases, Mayo Medical School, Rochester, Minnesota, United States of America.
Erhan
E
Ararat
Frank V
FV
Brozovich
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000033:anatomy & histology; D002216:Captopril / Q000627:therapeutic use; D004789:Enzyme Activation; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D019808:Losartan / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000503:physiopathology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007527:Isoenzymes; D002216:Captopril; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D019808:Losartan