Pyrrolidine Dithiocarbamate Down-regulates Vascular Matrix Metalloproteinases and Ameliorates Vascular Dysfunction and Remodelling in Renovascular Hypertension

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2011 Mar 26

PMID 21434884

Citations 17

Authors

S B A Cau

D A Guimaraes

E Rizzi

C S Ceron

L L Souza

C R Tirapelli

R F Gerlach

J E Tanus-Santos

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Mounting evidence implicates matrix metalloproteinase (MMP) in the vascular dysfunction and remodelling associated with hypertension. We tested the hypothesis that treatment with pyrrolidine dithiocarbamate (PDTC), which interferes with NF-κB-induced MMPs gene transcription, could exert antihypertensive effects, prevent MMP-2 and MMP-9 up-regulation, and protect against the functional alterations and vascular remodelling of two-kidney, one clip (2K1C) hypertension.

Experimental Approach: Sham-operated or hypertensive rats were treated with vehicle or PDTC (100 mg·Kg(-1) ·day(-1)) by gavage for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Aortic rings were isolated to assess endothelium-dependent relaxations. Quantitative morphometry of structural alterations of the aortic wall was carried out in haematoxylin/eosin sections. Formation of vascular reactive oxygen species (ROS), and inducible (i) NOS and phosphorylated-p65 NF-κB subunit expression were measured in the aortas. MMP-2 and MMP-9 aortic levels and gelatinolytic activity were determined by gelatin and in situ zymography and by immunofluorescence.

Key Results: Treatment with PDTC attenuated the increases in SBP and prevented the endothelial dysfunction associated with 2K1C hypertension. Moreover, PDTC reversed the vascular aortic remodelling, the increases in aortic ROS levels and in iNOS and phosphorylated-p65 NF-κB expression found in 2K1C rats. These effects were associated with attenuation of 2K1C up-regulation of aortic MMP-2 and MMP-9 levels and gelatinolytic activity.

Conclusion And Implications: These findings suggest that PDTC down-regulates vascular MMPs and ameliorates vascular dysfunction and remodelling in renovascular hypertension, thus providing evidence supporting the suggestion that PDTC is probably a good candidate to be used to treat hypertension.

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References

Browatzki M, Larsen D, Pfeiffer C, Gehrke S, Schmidt J, Kranzhofer A . Angiotensin II stimulates matrix metalloproteinase secretion in human vascular smooth muscle cells via nuclear factor-kappaB and activator protein 1 in a redox-sensitive manner. J Vasc Res. 2005; 42(5):415-23. DOI: 10.1159/000087451. View

Muller D, Dechend R, Mervaala E, Park J, Schmidt F, Fiebeler A . NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension. 2000; 35(1 Pt 2):193-201. DOI: 10.1161/01.hyp.35.1.193. View

Ceron C, Castro M, Rizzi E, Montenegro M, Fontana V, Salgado M . Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase-2 activity and expression in a model of renovascular hypertension. Br J Pharmacol. 2010; 160(1):77-87. PMC: 2860208. DOI: 10.1111/j.1476-5381.2010.00678.x. View

Cauwe B, Van den Steen P, Opdenakker G . The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol. 2007; 42(3):113-85. DOI: 10.1080/10409230701340019. View

Zahradka P, Werner J, Buhay S, Litchie B, Helwer G, Thomas S . NF-kappaB activation is essential for angiotensin II-dependent proliferation and migration of vascular smooth muscle cells. J Mol Cell Cardiol. 2002; 34(12):1609-21. DOI: 10.1006/jmcc.2002.2111. View

Lemarie C, Tharaux P, Esposito B, Tedgui A, Lehoux S . Transforming growth factor-alpha mediates nuclear factor kappaB activation in strained arteries. Circ Res. 2006; 99(4):434-41. DOI: 10.1161/01.RES.0000237388.89261.47. View

Watts S, Rondelli C, Thakali K, Li X, Uhal B, Pervaiz M . Morphological and biochemical characterization of remodeling in aorta and vena cava of DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol. 2007; 292(5):H2438-48. DOI: 10.1152/ajpheart.00900.2006. View

Beswick R, Zhang H, Marable D, Catravas J, Hill W, Webb R . Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension. 2001; 37(2 Pt 2):781-6. DOI: 10.1161/01.hyp.37.2.781. View

van der Heiden K, Cuhlmann S, Luong L, Zakkar M, Evans P . Role of nuclear factor kappaB in cardiovascular health and disease. Clin Sci (Lond). 2010; 118(10):593-605. DOI: 10.1042/CS20090557. View

10.

Flamant M, Placier S, Dubroca C, Esposito B, Lopes I, Chatziantoniou C . Role of matrix metalloproteinases in early hypertensive vascular remodeling. Hypertension. 2007; 50(1):212-8. DOI: 10.1161/HYPERTENSIONAHA.107.089631. View

11.

Kandasamy A, Chow A, Ali M, Schulz R . Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix. Cardiovasc Res. 2009; 85(3):413-23. DOI: 10.1093/cvr/cvp268. View

12.

Guo R, Yang L, Wang H, Liu B, Wang L . Angiotensin II induces matrix metalloproteinase-9 expression via a nuclear factor-kappaB-dependent pathway in vascular smooth muscle cells. Regul Pept. 2008; 147(1-3):37-44. DOI: 10.1016/j.regpep.2007.12.005. View

13.

Chow A, Cena J, Schulz R . Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol. 2007; 152(2):189-205. PMC: 1978261. DOI: 10.1038/sj.bjp.0707344. View

14.

Castro M, Rizzi E, Prado C, Rossi M, Tanus-Santos J, Gerlach R . Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. Matrix Biol. 2009; 29(3):194-201. DOI: 10.1016/j.matbio.2009.11.005. View

15.

Lemarie C, Tharaux P, Lehoux S . Extracellular matrix alterations in hypertensive vascular remodeling. J Mol Cell Cardiol. 2009; 48(3):433-9. DOI: 10.1016/j.yjmcc.2009.09.018. View

16.

Clark I, Swingler T, Sampieri C, Edwards D . The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol. 2008; 40(6-7):1362-78. DOI: 10.1016/j.biocel.2007.12.006. View

17.

Hong H, Loh S, Yen M . Suppression of the development of hypertension by the inhibitor of inducible nitric oxide synthase. Br J Pharmacol. 2000; 131(3):631-7. PMC: 1572360. DOI: 10.1038/sj.bjp.0703603. View

18.

Rodriguez-Iturbe B, Ferrebuz A, Vanegas V, Quiroz Y, Mezzano S, Vaziri N . Early and sustained inhibition of nuclear factor-kappaB prevents hypertension in spontaneously hypertensive rats. J Pharmacol Exp Ther. 2005; 315(1):51-7. DOI: 10.1124/jpet.105.088062. View

19.

Intengan H, Schiffrin E . Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001; 38(3 Pt 2):581-7. DOI: 10.1161/hy09t1.096249. View

20.

MARTINEZ-MALDONADO M . Pathophysiology of renovascular hypertension. Hypertension. 1991; 17(5):707-19. DOI: 10.1161/01.hyp.17.5.707. View