Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats

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Abstract
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 (SHRs). The mechanisms for this selective effect are largely unknown. We investigated the effects of HO-1 inducer, hemin, on the HO/CO-soluble gyanylyl cyclase (sGC)/cGMP system in the aorta of prehypertensive (4-week-old) young and adult SHRs as well as age-matched Wistar-Kyoto rats (WKYs). Reduced expressions of HO-1, HO-2, and sGC proteins associated with depressed HO activity and cGMP levels were detected in young SHRs. These deficiencies were significantly reversed by hemin treatment. Macrophage infiltration of vascular tissues was more significant in adult SHRs than adult WKYs, but invisible in young SHRs and WKYs. Hemin treatment did not alter macrophage infiltration of vascular tissues in young SHRs. The same hemin administration resulted in a significant decrease in BP (from 148.6 ± 3.2 to 125.8 ± 2.6 mmHg, P < .01) in young SHRs, but not in prehypertensive or adult SHRs or WKYs of all ages. The HO inhibitor zinc protoporphyrin abrogated the hemin effect in young SHRs. Aortic tissues became desensitized to YC-1, an activator sGC, in adult SHRs. Thus, in young SHRs the expression and function of the HO/CO-sGC/cGMP system were suppressed, constituting a pathogenic mechanism for the development of hypertension. In adult SHRs, the HO/CO-sGC/cGMP system appeared normal, but desensitization of the sGC/cGMP pathway caused hypertension to prevail.