Angiotensin II Destabilizes Coronary Plaques in Watanabe Heritable Hyperlipidemic Rabbits

Abstract

Objective Increased plasma concentrations of angiotensin II (Ang II) have been implicated in many cardiovascular diseases such as atherosclerosis, aortic aneurysms and myocardial infarction in humans. However, it is not known whether high levels of plasma Ang II affect coronary plaque stability and subsequent myocardial infarction. The current study was designed to examine whether elevated plasma Ang II can directly induce coronary events such as acute coronary syndrome. Approach and Results To examine the above hypothesis, we infused Ang II [100 ng/min/kg (low group) and 200 ng/min/kg (high group)] or saline vehicle via osmotic minipumps into WHHL rabbits, a model of human familial hypercholesterolemia and atherosclerosis. Infusion of Ang II resulted in mortality rates of 50% and 92% in the low- and high-Ang II groups, respectively, while there were no deaths in the vehicle group. Pathological analysis revealed that Ang II-infused WHHL rabbits that died showed myocardial infarction. Furthermore, Ang II-infused WHHL rabbits exhibited coronary plaque erosion and rupture that were associated with thrombosis. Conclusions These findings suggest that increased blood levels of Ang II can destabilize coronary plaques and trigger the thrombosis, which possibly induces myocardial infarction. The model described in this study provides a novel means for the study of human acute coronary syndrome.

Renovascular Hypertension Aggravates Atherosclerosis in Cholesterol-Fed Rabbits

“…It is worth noting that in the HTN group, the advanced lesions contained calcified foci but lacked typical necrotic/lipid cores or plaque rupture. These features are different from AngII-infused WHHL rabbits, in which coronary erosion/rupture can be induced [17]. On the other hand, HTN WHHL rabbits exhibited a higher frequency of intraplaque hemorrhages in the aorta [30].…”

“…BP and heart rate were examined every for 4 weeks during the experiment as described previously [16, 17]. To avoid environmental stress, BP measurements were conducted in a separate room.…”

Atherosclerotic Plaque Rupture

“…Interestingly, the authors also describe some cases of plaque erosion as a cause of myocardial infarction. If shown that the response to pharmacological treatment mirrors what we see in humans, then the model described by Li et al 54 would constitute a compelling model for testing of new, potentially plaque-stabilizing drugs that could prevent myocardial infarction.…”

“…Importantly, it reflects pharmacological effects of drugs that are known to stabilize plaques in humans. 47 Recently, Li et al 54 have reported coronary plaque rupture/erosion in Watanabe Heritable Hyperlipidemia rabbits infused with angiotensin II. The authors provide strong histological evidence of plaque rupture, including fibrous cap break, luminal thrombosis, intraplaque hemorrhage, and a high percentage of mortality caused by myocardial infarction.…”

Role of a RhoA/ROCK-Dependent Pathway on Renal Connexin43 Regulation in the Angiotensin II-Induced Renal Damage

“…A small (1 cm) cut was made in the mid scapular region and an osmotic pump was implanted (Alzet, Cupertino, CA, USA), and subsequently the wound was sutured. Pumps with a release rate of 160 ng/min per day for 6 weeks, were loaded with a high-dose of AngII dissolved in saline [59,60]. Pumps were kept in the animals for the duration of the experimental treatment.…”