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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-08-2608.
Submitted August 26, 2002
Accepted December 16, 2002
Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats
Joseph Fomusi Ndisang, Lingyun Wu, Weimin Zhao, and Rui Wang*
Department of Physiology, University of Saskatchewan, Saskatoon, SK, Canada
Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
* Corresponding author; email: wangrui{at}duke.usask.ca.
Heme oxygenase (HO) and carbon monoxide (CO) have been implicated in the modulation of various cardiovascular functions including blood pressure (BP) regulation. Up-regulating the HO/CO system lowers BP in young (8-week old), but not in adult (20-week old), spontaneously hypertensive rats (SHR). The mechanisms for this selective effect are largely unknown. We investigated the effects of HO-1 inducer, hemin, on the HO/CO-sGC/cGMP system in the aorta of pre-hypertensive (4-week old), young, and adult SHR as well as age-matched Wistar-Kyoto rats (WKY). Reduced expressions of HO-1, HO-2, and sGC proteins associated with depressed HO activity and cGMP levels, were detected in young SHR. These deficiencies were significantly reversed by hemin treatment. Macrophage infiltration of vascular tissues was more significant in adult SHR than adult WKY, but invisible in young SHR and WKY. Hemin treatment did not alter macrophage infiltration of vascular tissues in young SHR. The same hemin administration resulted in a significant decrease in BP (from 148.6±3.2 to 125.8±2.6 mmHg, p<0.01) in young SHR, but not in pre-hypertensive or adult SHR or WKY of all ages. HO inhibitor, zinc protoporphyrin, abrogated the hemin effect in young SHR. Aortic tissues became desensitized to YC-1, an activator sGC, in adult SHR. Thus, in young SHR the expression and function of HO/CO-sGC/cGMP system were suppressed, constituting a pathogenic mechanism for the development of hypertension. In adult SHR the HO/CO-sGC/cGMP system appeared normal, but desensitization of sGC/cGMP pathway caused hypertension to prevail.
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