Published Online
on February 17, 2003

A more recent version of this article appeared on February 25, 2003

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Submitted on August 9, 2002
Revised on November 7, 2002
Accepted on November 8, 2002

Temporal Response and Localization of Integrins 1 and 3 in the Heart After Myocardial Infarction. Regulation by Cytokines

Mei Sun MD, PhD, M. Anne Opavsky MD, PhD, Duncan J. Stewart MD, Marlene Rabinovitch MD, Fayez Dawood DVM, Wen-Hu Wen MD, and Peter P. Liu MD^*

From the Heart and Stroke/Richard Lewar Centre of Excellence and Division of Cardiology, University Health Network (M.S., F.D., W.-H.W., P.P.L); Research Institute, The Hospital for Sick Children (M.A.O., M.R.); and Division of Cardiology, St Michael's Hospital (D.J.S.), University of Toronto, Canada.

^* To whom correspondence should be addressed. E-mail: peter.liu{at}utoronto.ca.

Background--Integrins are involved in structural remodeling and tissue repair. This study aimed to elucidate the role of the -integrins in cardiac remodeling after myocardial infarction (MI).

Methods and Results--The MI model was created by ligation of the left anterior descending coronary artery in rats. We detected cardiac integrins 1 and 3 gene expression (quantitative in situ hybridization) and protein production (Western blot and immunohistochemistry) and potential regulation by tumor necrosis factor (TNF) using neonatal ventricular myocytes and TNF^-/- knockout mice. Integrins 1 and 3 gene expression and protein production were low in sham-operated hearts. After MI, the 1 and 3 mRNA and proteins were significantly increased at the site of MI at day 3, reached a peak at day 7, and gradually declined thereafter. Integrin 1A localized primarily in fibroblasts and inflammatory cells, 1D localized in myocytes, and integrin 3 was associated primarily with endothelial and smooth muscle cells in peri-infarct vessels. In cultured myocytes, there was isoform transition from the adult 1D to the fetal 1A on exposure to TNF-. This was confirmed in vivo in the peri-infarct myocytes, but the transition was voided in TNF^-/--knockout mice.

Conclusions--Integrins 1 and 3 are significantly activated in the infarcted myocardium. Integrin 1 is active particularly at sites of inflammation and fibrosis, whereas integrin 3 localizes to vessels in the peri-infarct zone in a temporally coordinated manner. Integrin 1D to 1A isoform transition in myocytes is regulated by TNF-.

Key words: myocardial infarction • integrins • remodeling • angiogenesis • tumor necrosis factor-

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