Korean J Physiol Pharmacol.  2009 Aug;13(4):309-313. 10.4196/kjpp.2009.13.4.309.

Heme Oxygenase-1 Induced by Aprotinin Inhibits Vascular Smooth Muscle Cell Proliferation Through Cell Cycle Arrest in Hypertensive Rats

Affiliations
  • 1Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 705-717, Korea. yjkang@med.yu.ac.kr
  • 2Department of Thoracic and Cardiovascular Surgery, College of Medicine, Yeungnam University, Daegu 705-717, Korea.
  • 3Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717, Korea.

Abstract

Spontaneous hypertensive rats (SHR) are an established model of genetic hypertension. Vascular smooth muscle cells (VSMC) from SHR proliferate faster than those of control rats (Wistar-Kyoto rats; WKY). We tested the hypothesis that induction of heme oxygenase (HO)-1 induced by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats. Aprotinin treatment inhibited VSMC proliferation in SHR more than in normotensive rats. These inhibitory effects were associated with cell cycle arrest in the G1 phase. Tin protoporphyrin IX (SnPPIX) reversed the anti-proliferative effect of aprotinin in VSMC from SHR. The level of cyclin D was higher in VSMC of SHR than those of WKY. Aprotinin treatment downregulated the cell cycle regulator, cyclin D, but upregulated the cyclin-dependent kinase inhibitor, p21, in VSMC of SHR. Aprotinin induced HO-1 in VSMC of SHR, but not in those of control rats. Furthermore, aprotinin-induced HO-1 inhibited VSMC proliferation of SHR. Consistently, VSMC proliferation in SHR was significantly inhibited by transfection with the HO-1 gene. These results indicate that induction of HO-1 by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats.

Keyword

Aprotinin; Hypertension; Proliferation; Heme oxygenase-1; Cell cycle arrest

MeSH Terms

Animals
Aprotinin
Cell Cycle
Cell Cycle Checkpoints
Cell Proliferation
Cyclin D
G1 Phase
Heme
Heme Oxygenase (Decyclizing)
Heme Oxygenase-1
Hypertension
Metalloporphyrins
Muscle, Smooth, Vascular
Phosphotransferases
Protoporphyrins
Rats
Tin
Transfection
Aprotinin
Cyclin D
Heme
Heme Oxygenase (Decyclizing)
Heme Oxygenase-1
Metalloporphyrins
Phosphotransferases
Protoporphyrins
Tin
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