p38 MAP kinase activity is correlated with angiotensin II type 1 receptor blocker-induced left ventricular reverse remodeling in spontaneously hypertensive heart failure rats.
BACKGROUND
Angiotensin II type 1 receptor blocker L-158,809 (ARB) induces reverse left ventricular (LV) remodeling in spontaneously hypertensive heart failure (SHHF) rats. However, the signaling mechanism that mediates ARB-induced reverse LV remodeling remains unclear. The present study was to determine if changes in mitogen-activated protein kinase (MAPK, including ERK, JNK, and p38) signaling correlate with ARB-elicited reversal of cardiac hypertrophy in SHHF rats.


RESULTS
In 1 set of experiments, 5-month-old lean female SHHF rats were treated with L-158,809 (ARB) or the vasodilator hydralazine (HYD) for 1 month, respectively. In a second set of experiments, 5-month-old SHHF rats were treated with ARB for 6 months or 1 month and then with HYD for 5 months. Either ARB or HYD normalized left ventricular end systolic pressure in SHHF rats relative to normotensive control Wistar Furth (WF) rats at both 6 and 11 months of age, but only ARB reduced heart-to-body weight ratio in SHHF rats to control level. Western blot analysis showed that cardiac p38 MAPK activity was markedly increased in 6-month-old SHHF rats, but dramatically reduced in 11-month-old SHHF rats compared with WF rats, as indicated by the levels of phosphorylated form of p38. The alterations in p38 activity were completely reversed by ARB treatment but not by HYD treatment.


CONCLUSIONS
ARB restored normal cardiac p38 activity, which coincided with ARB-induced reverse LV remodeling in SHHF rats, suggesting a strong correlation between p38 signaling and cardiac remodeling.
Liang
Qiangrong
Q
University of South Dakota, School of Medicine, Cardiovascular Research Institute-South Dakota Health Research Foundation, Sioux Falls, South Dakota 57105, USA.
Elson
Andrew C
AC
Gerdes
A Martin
AM
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D005260:Female; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics; D011920:Rats, Inbred WF; D014665:Vasodilator Agents / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D014665:Vasodilator Agents; D006830:Hydralazine; D048051:p38 Mitogen-Activated Protein Kinases