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Myocardial angiotensin II receptor expression and ischemia-reperfusion injury

Department of Medicine, University of Florida, VA Medical Center, Gainesville, FL, USA

Dayuan Li

Department of Medicine, University of Florida, VA Medical Center, Gainesville, FL, USA

M Ian Phillips

Department of Physiology, University of Florida

Paulette Mehta

Department of Pediatrics, Gainesville, FL, USA

Jawahar L Mehta

Department of Medicine, University of Florida, Department of Physiology, University of Florida, VA Medical Center, Gainesville, FL, USA

The renin-angiotensin system plays an important role in myocardial ischemia-reper-fusion injury. Angiotensin II (Ang II) contributes to the evolution of ischemic coronary events through its hemodynamic, hemostatic and mitogenic effects. Angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor antagonists have been shown to be cardioprotective in experimental animal models, with ischemia-reperfusion injury and in patients with congestive heart failure. Ang II receptors include at least two different subtypes, AT₁ and AT₂. Both AT₁ and AT₂ are expressed in the rat heart. Myocardial AT₁ receptor density increases in association with ACE expression, and AT₁ receptor activation is related to collagen formation following myocardial infarction in rats. Studies from the authors' laboratory have shown significant myocardial dysfunction in association with a concurrent increase in AT₁ receptor expression in the rat myocardium immediately following a brief period of ischemia and reperfusion. Application of antisense oligodeoxynucleotides (AS-ODN) directed at AT₁ receptor messenger RNA and AT₁ receptor antagonist, losartan, significantly attenuates myocardial dysfunction induced by ischemia-reperfusion in the isolated rat heart. These observations suggest that myocardial AT₁ receptor expression is involved in myocardial dysfunction following ischemia-reperfusion. Unlike losartan, which upregulates the plasma Ang II level, administration of AS-ODN does not affect plasma Ang II level. Although the reason for this is not clear, the difference in plasma Ang II levels implies that AS-ODN may be, at least theoretically, more beneficial than losartan in limiting ischemia-reperfusion-induced cardiac dysfunction. Apoptosis, or programmed cell death, also contributes to the outcome of myocardial ischemia-reperfusion injury. Recent studies from the authors' laboratory have demonstrated that Ang II induces apoptosis in cultured human coronary artery endothelial cells via activation of AT₁ receptors and this can be blocked by losartan. These observations collectively underscore the importance of myocardial AT₁ receptor expression in ischemia-reperfusion injury.

Key Words: angiotensin II • antisense oligodeoxynucleotides • apoptosis • AT1 receptors • ischemia-reperfusion

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