Journal
CRITICAL CARE MEDICINE
Volume 40, Issue 11, Pages 3026-3033Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0b013e31825fd7da
Keywords
autophagy; cardiac remodeling; fractalkine; heart failure; myocardial ischemia; resveratrol
Categories
Funding
- National Natural Science Foundation of China [81170146]
- National Program on Key Basic Research Project [2012CB945100]
- Natural Science Foundation of Guangdong Province, China [S2011030003134]
- Department of Education of Guangdong Provincial Government, China
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Objectives: To test the hypothesis that resveratrol would improve cardiac remodeling by inhibiting the detrimental effects of fractalkine. We previously reported that fractalkine exacerbates heart failure. Furthermore, this study sought to determine whether resveratrol targets fractalkine to improve myocardial ischemia and cardiac remodeling. Design: Randomized and controlled laboratory investigation. Setting: Research laboratory. Subjects: Neonatal rat cardiac cells and C57BL/6 mice. Interventions: Cardiac cells were treated with recombinant mouse soluble fractalkine for 24 hrs or pretreated with 25 mu M resveratrol. Cardiomyocytes were exposed to anoxia/reoxygenation, H2O2, or pretreatment with resveratrol. Ex vivo murine hearts were perfusioned with soluble fractalkine or pretreated with resveratrol after global ischemia. Mice were subjected to the left coronary artery ligation to induce myocardial infarction and randomized to treatment with resveratrol or vehicle alone for 42 days. Measurements and Main Results: In a murine myocardial infarction model, we found that resveratrol increased survival and delayed the progression of cardiac remodeling evaluated by serial echocardiography. At 6 wks, the heart weight/body weight ratio, lung weight/body weight ratio, and old infarct size were significantly smaller in resveratrol-treated mice than in untreated myocardial infarction mice. In cultures of neonatal rat cells, exposure to soluble fractalkine increased the atrial natriuretic peptide expression by cardiomyocytes, matrix metalloproteinase-9 and procollagen expression by fibroblasts, and intercellular adhesion molecule-1 expression by microvascular endothelial cells, while it decreased autophagy in cardiomyocytes. All these effects were blocked by coculture with resveratrol. The methyl thiazolyl tetrazolium assay showed that soluble fractalkine reduced the viability of cultured cardiomyocytes during exposure to anoxia/reoxygenation or H2O2, while pretreatment with resveratrol blocked this effect. Perfusion of ex vivo murine hearts with soluble fractalkine after global ischemia led to an increase of infarct size, which was prevented by pretreatment with resveratrol. Conclusion: Resveratrol alleviates the deleterious effects of fractalkine on myocardial ischemia and thus reduces subsequent cardiac remodeling. (Crit Care Med 2012; 40: 3026-3033)
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