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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:61.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

The Mechanistic Basis for the Disparate Effects of Angiotensin II on Coronary Collateral Growth

Ryan Reed; Christopher Kolz; Barry Potter; Petra Rocic

From the Department of Integrative Medical Sciences (C.K., P.R.), Northeastern Ohio Universities College of Medicine, Rootstown; and the Departments of Physiology (B.P.) and Pharmacology (R.R.), Louisiana State University Health Sciences Center, New Orleans.

Correspondence to Petra Rocic, PhD, Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, 4209 State Route 44, PO Box 95, Rootstown, OH 44275. E-mail procic{at}neoucom.edu

Abstract

Objective— We hypothesize that controversial effects of angiotensin II (Ang II) are attributable to its regulation of reactive oxygen species (ROS) and ROS-dependent signaling.

Methods and Results— Coronary collateral growth (CCG) was stimulated in normal (WKY) and syndrome X (JCR) rats by transient/repetitive ischemia (RI). Blood flow was measured in the normal (NZ) and the collateral-dependent (CZ) zone. In WKY, RI increased CZ flow (0.84 mL/min/g), but RI+subpressor Ang II increased it more (1.24 mL/min/g). This was associated with transient p38 and sustained Akt activation. A hypertensive dose of Ang II decreased CZ flow (0.69 mL/min/g), which was associated with sustained p38 and transient Akt activation. AT1R blockade by candesartan abrogated CZ flow in WKY (0.58 mL/min/g), reduced myocardial superoxide, and blocked p38 and Akt activation. RI-induced CZ flow in JCR was significantly decreased compared with WKY (0.12 mL/min/g), associated with a large increase in superoxide and lack of p38 and Akt activation. CZ flow in JCR was partially restored by candesartan (0.45 mL/min/g), accompanied by reduction in superoxide and partial restoration of p38 and Akt activation.

Conclusion— Ang II/AT1R blockade, at least in part, regulates CCG via generating optimal ROS amounts and activating redox-sensitive signaling.

Ang II regulates repetitive ischemia (RI)-induced coronary collateral growth (CCG) via ROS generation and redox-sensitive signaling. In normal oxidative stress, AT1R blockade decreases CCG; in elevated oxidative stress (metabolic syndrome), AT1R blockade rescues CCG by normalizing oxidative stress and activating p38 and Akt.

Key Words: Angiotensin II • syndrome X • coronary disease • signal transduction

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