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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-08-2608.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3893-3900
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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
From the Department of Physiology and Department of
Pharmacology, University of Saskatchewan, Saskatoon, SK,
Canada.
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.
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