Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 48, Issue 4, Pages 765-772Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2010.01.006
Keywords
NADPH oxidase; Aging; Matrix metalloproteases; Angiotensin II; Remodeling; Oxidative stress
Categories
Funding
- NIH
- British Heart Foundation [CH/99001]
- British Heart Foundation [RG/08/011/25922] Funding Source: researchfish
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Increased activation of the renin-angiotensin-aldosterone system (RAAS) and an increase in oxidative stress are both implicated in age-related cardiac remodeling but their precise interrelationship and linkage to underlying molecular and cellular abnormalities remain to be defined. Recent studies indicate that NADPH oxidases are major sources of oxidative stress and are activated by the RAAS. This study investigated the relationship between the NADPH oxidase system, age-related cardiac remodeling and its underlying mechanisms. We studied male Fisher 344 cross Brown Norway rats aged 2 months (young rats), 8 months (young adult rats) or 30 months (old rats). Aging-dependent increases in blood pressure, cardiomyocyte area, coronary artery remodeling and cardiac fibrosis were associated with increased myocardial NADPH oxidase activity attributable to the Nox2 isoform. These changes were accompanied by evidence of local RAAS activation, increased expression of connective tissue growth factor (CTGF) and TGF-beta 1, and a significant activation of MMP-2 and MT1-MMP. The changes in old rats were replicated in 8 month old rats that were chronically treated with angiotensin II for 28 days. Increased RAAS activation may drive age-related cardiac remodeling through the activation of Nox2 NADPH oxidase and subsequent increases in MMP activation, fibrosis and cardiomyocyte hypertrophy. (c) 2010 Elsevier Ltd. All rights reserved.
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