Alterations in Heme Oxygenase/Carbon Monoxide System in Pulmonary Arteries in Hypertension

Abstract

Enhancement of the heme oxygenase/carbon monoxide (HO/CO) system has been shown to lower blood pressure (BP) in young (8 weeks), but not in adult (20 weeks) spontaneously hypertensive (SHR) rats. The reasons for this selective effect still remain puzzling. We investigated the effects of hemin on the HO/CO system of the pulmonary artery (PA) in SHR and Wistar-Kyoto (WKY) rats at different ages and evaluated the hemin-dependent changes in sGC and cGMP pathways. Hemin administration resulted in an evident reduction of BP (from 148.6 ± 3.2 to 125.8 ± 2.6 mmHg, P < 0.01) in young, but not in prehypertensive (4 weeks) or adult SHR or WKY rats at all ages. Coadministration of the HO inhibitor, chromium mesoporphyrin, with hemin, cancelled the BP-lowering effect of hemin. Remarkably, lower expression levels of HO-1, HO-2, and sGC paralleled with reduced HO activity and cGMP content were observed in PA from 8-week SHR rats, but not from adult SHR or WKY rats of all ages. Interestingly, hemin treatment restored these deficiencies, although the expression level of non-inducible HO-2 protein remained unchanged. We conclude that in young and prehypertensive SHR rats, an impaired HO/CO-sGC/cGMP system in the PA might be indicative of the pathogenesis and development of hypertension. In contrast, the HO/CO system in the PA of adult SHR rats was upregulated as a compensatory reaction to elevated BP and desensitization of the downstream targets of the sGC/cGMP pathway occurred.

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References

Wang R. Two’s company three’s a crowd. Can hydrogen sulphide be the 3^rd endogenous gaseous transmitter? FASEB J 16 : 1792–1798, 2002.

Wang R, Wang ZZ, Wu L. Carbon monoxide-induced vasorelaxation and the underlying mechanisms. Br J Pharmacol 121 : 927–934, 1997.

Kun C, Wang R. Carbon monoxide, vascular contractility and K⁺ channels. In: Wang R, Ed. Carbon Monoxide and Cardiovascular Functions. Boca Raton, FL: CPC Press, pp83–109, 2002.

Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA. Guanylyl cyclases and signalling by cyclic GMP. Pharmacol Rev 52 : 375–414, 2000.

Ndisang JF, Masini E, Mannaioni PF, Wang R. Carbon monoxide and cardiovascular inflammation. In: Wang R, Ed. Carbon Monoxide and Cardiovascular Functions. Boca Raton, FL: CPC Press, pp165–180, 2002.

Johnson RA, Lavesa M, Askari B, Abraham NG, Nasjletti A. A heme oxygenase product, presumably carbon monoxide, mediates a vasodepressor function in rats. Hypertension 25 : 166–169, 1995.

Johnson RA, Colombari E, Colombari DS, Lavesa M, Talman WT, Nasjletti A. Role of endogenous carbon monoxide in central regulation of arterial pressure. Hypertension 30 : 962–967, 1997.

Morita T, Kourembanas S. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. J Clin Invest 96 : 2676–2682, 1995.

Johnson RA, Kozma F, Colombari E. Carbon monoxide: From toxin to endogenous modulator of cardiovascular functions. Braz J Med Biol Res 32 : 1–14, 1999.

10.

Brian JE Jr, Heistad DD, Faraci FM. Effect of carbon monoxide on rabbit cerebral arteries. Stroke 25 : 639–643, 1994.

11.

Leffler CW, Masjletti A, Yu C, Johnson RA, Fedinec AL, Walker N. Carbon monoxide and cerebral micro-vascular tone in newborn pigs. Am J Physiol 276 : H1641–H1646, 1999.

12.

Villamor E, Perez-Vizcaino F, Cogolludo AL, Conde-Oviedo J, Zaragoza-Arnaez F, Lopez-Lopez JG, Tamargo J. Relaxant effects of carbon monoxide compared with nitric oxide in pulmonary and systemic vessels of newborn piglets. Pediatr Res 48 : 546–553, 2000.

13.

Itani MM, Talerico MG, Pino PA, Burke-Wolin T. Early regulatory changes in rat pulmonary artery of renin-dependent systemic hypertension models. Am J Respir Cell Mol Biol 15 : 467–472, 1996.

14.

Janssens SP, Kachoris C, Parker WL, Hales CA, Haupert GT Jr. Hypothalamic Na+,K(+)-ATPase inhibitor constricts pulmonary arteries of spontaneously hypertensive rats. J Cardiovasc Pharmacol 22 : S42– S46, 1993.

15.

Kohno M, Horio T, Yokokawa K, Akioka K, Ikeda M, Takeda T. Pulmonary arterial brain natriuretic peptide concentration and cardiopulmonary hemodynamics during exercise in patients with essential hypertension. Metabolism 41 : 1273–1275, 1992.

16.

Yaghi A, Webb CD, Scott JA, Mehta S, Bend JR, McCormack DG. Cytochrome P450 metabolites of arachidonic acid but not cyclooxygenase-2 metabolites contribute to the pulmonary vascular hyporeactivity in rats with acute Pseudomonas pneumonia. J Pharmacol Exp Ther 297 : 479–488, 2001.

17.

Sacerdoti D, Escalante B, Abraham NG, McGiff JC, Levere RD, Schwartzman ML. Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats. Science 243 : 388–390, 1989.

18.

Levere RD, Martasek P, Escalante B, Schwartzman ML, Abraham NG. Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats. J Clin Invest 86 : 213–219, 1990.

19.

Ndisang JF, Zhao W, Wang R. Selective regulation of blood pressure by heme oxygenase-1 in hypertension. Hypertension 40 : 315–321, 2002.

20.

Ndisang JF, Wang R, Vannacci A, Marzocca C, Fantappie O, Mazzanti R, Mannaioni PF, Masini E. Haeme oxygenase-1 and cardiac anaphylaxis. Br J Pharmacol 134 : 1689–1696, 2001.

21.

Vreman HJ, Ekstrand BC, Stevenson DK. Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity. Pediatr Res 33 : 195–200, 1993.

22.

Kushida T, Quan S, Yang L, Ikehara S, Kappas A, Abraham NG. A significant role for the heme oxygenase-1 gene in endothelial cell cycle progression. Biochem Biophys Res Commun 291 : 68–75, 2002.

23.

Ndisang JF, Gai P, Berni L, Mirabella C, Baronti R, Mannaioni PF, Masini E. Modulation of the immunological response of guinea pig mast cells by carbon monoxide. Immunopharmacology 43 : 65–73, 1999.

24.

Omata K, Abraham NG, Escalante B, Schwartzman ML. Age-related changes in renal cytochrome P-450 arachidonic acid metabolism in spontaneously hypertensive rats. Am J Physiol 262 : F8–F16, 1992.

25.

Kawashima A, Oda Y, Yachie A, Koizumi S, Nakanishi I. Heme oxygenase-1 deficiency: The first autopsy case. Hum Pathol 33 : 125–130, 2002.