Crosstalk between the heme oxygenase system, aldosterone, and phospholipase C in hypertension.
BACKGROUND
Aldosterone is a mineral corticoid hormone that is produced in response to angiotensin-II, and like angiotensin-II, stimulates inflammation, oxidative stress, and fibrosis by activating nuclear factor-kappaB and activating protein-1. Recent evidence, however, indicates that aldosterone stimulates phospholipase C and activates nuclear factor-kappaB and activating protein-1. Although the heme oxygenase system is cytoprotective, its effects on aldosterone-phospholipase C signaling in deoxycorticosterone acetate (DOCA-salt) hypertension, a model of aldosteronism, and spontaneously hypertensive rat, a genetic model of human essential hypertension, have not been fully characterized.


METHODS
In the present study, the heme oxygenase inducer, hemin, was given to spontaneously hypertensive and deoxycorticosterone acetate hypertensive rats, and the effects on blood pressure, aldosterone, nuclear factor-kappaB, activating protein-1, phospholipase C, and inositol 1,4,5-triphosphate were examined.


RESULTS
Hemin therapy restored physiological blood pressure to spontaneously hypertensive rats (209.9 +/- 0.9 to 127.3 +/- 0.85 mmHg, n = 10, P < 0.01) and to deoxycorticosterone acetate salt hypertensive rats (195.7 +/- 1.8 vs.132.5 +/- 2.1 mmHg; P < 0.01, n = 10), but had no effect on age-matched normotensive Wistar-Kyoto or Sprague-Dawley strains. The antihypertensive effect was accompanied by enhanced heme oxygenase activity, upregulated cyclic guanosine monophosphate-protein kinase G signaling, increased superoxide dismutase activity, and the potentiation of total antioxidant capacity, whereas aldosterone, activating protein-1, and nuclear factor-kappaB were reduced. Furthermore, hemin suppressed phospholipase C activity, attenuated inositol 1,4,5-triphosphate, and reduced resting intracellular calcium in the aorta.


CONCLUSIONS
Collectively, our results suggest that the concomitant depletion of aldosterone, phospholipase C-inositol 1,4,5-triphosphate activity, resting intracellular calcium and the corresponding decline of inflammatory, and oxidative insults may account for the antihypertensive effects of hemin in deoxycorticosterone acetate hypertension and spontaneously hypertensive rats.
Ndisang
Joseph Fomusi
JF
Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. jon056@mail.usask.ca
Lane
Nina
N
Jadhav
Ashok
A
D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006427:Hemin / Q000009:adverse effects / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation
D000450:Aldosterone; D006427:Hemin; D015544:Inositol 1,4,5-Trisphosphate; D006419:Heme Oxygenase (Decyclizing); D017869:Cyclic GMP-Dependent Protein Kinases; D010738:Type C Phospholipases; D006152:Cyclic GMP; D002118:Calcium