Journal
JOURNAL OF CARDIAC FAILURE
Volume 12, Issue 6, Pages 479-486Publisher
CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS
DOI: 10.1016/j.cardfail.2006.04.006
Keywords
MAP kinase; hypertension; cardiac remodeling; heart failure
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Funding
- NCRR NIH HHS [P20 RR017662] Funding Source: Medline
- NHLBI NIH HHS [HL-62459] Funding Source: Medline
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Background: Angiotensin 11 type I 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. Methods and Results: In I set of experiments, 5-month-old lean female SHHF rats were treated with L-158,809 (ARB) or the vasodilator hydralazine (HYD) for I month, respectively. In a second set of experiments, 5-month-old SHHF rats were treated with ARB for 6 months or I 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 I I 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. Conclusion: 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.
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