Myocardial angiotensin II receptor expression and ischemia-reperfusion injury.
The renin-angiotensin system plays an important role in myocardial ischemia-reperfusion 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.
Yang
B
B
Department of Medicine, University of Florida, Gainesville, USA.
Li
D
D
Phillips
M I
MI
Mehta
P
P
Mehta
J L
JL
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011945:Receptors, Angiotensin / Q000096:biosynthesis*
D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D011945:Receptors, Angiotensin