Abstract
Angiotensin II (Ang II) is a potent stimulator of plasminogen activator inhibitor-1 (PAI-1) expression, which is an important regulator of pathogenesis of atherosclerosis. Rho-kinase, a downstream target protein of small GTP-binding protein Rho, plays a key role for various cellular functions. We evaluated the cardioprotective effects of a specific Rho-kinase inhibitor, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632), and an Ang II type 1 receptor antagonist, candesartan, on PAI-1 gene expression and cardiovascular remodeling in Ang II-induced hypertensive rats. Rats given Ang II alone (200 ng · kg−1 · min−1) were compared with rats also receiving Ang II plus Y-27632 or Ang II plus candesartan. Ang II-induced PAI-1 mRNA up-regulation in the left ventricle was inhibited by Y-27632 and candesartan. In addition, increased RhoA protein, Rho-kinase, and c-fos gene expression, and myosin light chain phosphorylation were suppressed by Y-27632 and candesartan. In contrast, Y-27632 had no effect on Ang II-stimulated phospho-p42/p44 extracellular signal-regulated kinases (ERK) and phospho-p70S6 kinase activities, which are reported to be involved in Ang II-induced protein synthesis. Moreover, activated Ang II-induced phosphorylation of ERK and p70S6 kinase were blocked by candesartan. Y-27632 or candesartan administration resulted in significant improvements in the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis. These results suggested that differential activation of Rho-kinase and ERK pathways may play a critical role in Ang II-induce PAI-1 gene expression, and up-regulation of Rho-kinase plays a key role in the pathogenesis of Ang II-induced hypertensive rats. Thus, inhibition of the Rho-kinase pathway may be at least a useful therapeutic strategy for treating cardiovascular remodeling.
Footnotes
- Abbreviations:
- ERK
- extracellular signal-regulated kinase
- Ang II
- angiotensin II
- ANGII-CAN
- angiotensin II-infused and candesartan-treated group
- ANGII-RHO
- angiotensin II-infused and Y-27632-treated group
- ANGII-V
- angiotensin II-infused group
- AP-1
- activator protein-1
- AT1
- angiotensin II receptor, type 1
- CON
- control group
- eNOS
- endothelial nitric oxide synthase
- ET-1
- endothelin-1
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- MLC
- myosin light chain
- LV
- left ventricle
- PAI-1
- plasminogen activator inhibitor-1
- PDGF
- platelet-derived growth factor
- RAS
- renin-angiotensin system
- RT-PCR
- reverse transcription-polymerase chain reaction
- SMCs
- smooth-muscle cells
- Received September 24, 2001.
- Accepted February 5, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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