Increase in heme oxygenase-1 levels ameliorates renovascular hypertension.
BACKGROUND
The heme oxygenase system (HO-1 and HO-2) catalyzes the conversion of heme to free iron, carbon monoxide (CO), a vasodepressor, and biliverdin, which is further converted to bilirubin, an antioxidant. HO-1 induction has been shown to suppress arachidonic acid metabolism by cytochrome P450 (CYP450) monooxygenases and cyclooxygenases (COX), and to decrease blood pressure in spontaneously hypertensive rats (SHR). The Goldblatt 2K1C model is a model of renovascular hypertension in which there is increased expression of COX-2 in the macula densa and increased renin release from the juxtaglomerular apparatus of the clipped kidney. We examined whether HO-1 overexpression, as a prophylactic approach, would attenuate renovascular hypertension and evaluated potential mechanisms that may account for its effect.


METHODS
2K1C rats were treated with cobalt protoporphyrin (CoPP) or tin mesoporphyrin (SnMP) one day before surgery and weekly for three weeks thereafter. We measured systolic blood pressure, HO activity, HO-1, HO-2, COX-1 and COX-2 protein expression, heme content, and nitrotyrosine levels as indices of oxidative stress. Urinary prostaglandin excretion (PGE2), plasma renin activity (PRA), and plasma aldosterone levels were also measured.


RESULTS
CoPP administration induced renal HO-1 expression by 20-fold and HO activity by 6-fold. This was associated with a reduction in heme content, nitrotyrosine levels, COX-2 expression and urinary PGE2 excretion, and attenuation of the development of hypertension in the 2K1C rats. There was no decrease in plasma renin activity; however, plasma aldosterone levels were significantly lower. In the 2K1C SnMP-treated rats, blood pressure was significantly higher than that of untreated 2K1C rats throughout the study, and the difference in the size of the smaller left clipped kidney compared to the nonclipped right kidney was significantly increased.


CONCLUSIONS
These findings define an action of prolonged HO-1 induction to interrupt and counteract the influence of the renin-angiotensin-aldosterone system (RAAS) to increase in blood pressure in the 2K1C model of renovascular hypertension. Multiple mechanisms include a decrease in oxidative stress as indicated by the decrease in cellular heme and nitrotyrosine levels, an anti-inflammatory action as evidenced by a decrease in COX-2 and PGE2, interference with the action of angiontensin II (Ang II) as evidenced by an increase in PRA in the face of a decrease in PGE2 and aldosterone, as well as the inhibition of aldosterone synthesis.
Botros
Fady T
FT
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Schwartzman
Michal L
ML
Stier
Charles T
CT
Goodman
Alvin I
AI
Abraham
Nader G
NG
D000450:Aldosterone / Q000097:blood; D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000652:urine; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006977:Hypertension, Renal / Q000378:metabolism*; D007606:Juxtaglomerular Apparatus / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009929:Organ Size; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; C055421:tin mesoporphyrin; C002744:3-nitrotyrosine; D014443:Tyrosine; D006418:Heme; D000450:Aldosterone; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D012083:Renin; D015232:Dinoprostone