Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor.

Abstract

BACKGROUND:

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have effects that extend beyond cholesterol reduction. We used an angiotensin (Ang) II-dependent model to test the hypothesis that cerivastatin ameliorates cardiac injury.

METHODS AND RESULTS:

We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from weeks 4 to 7 with cerivastatin (0.5 mg/kg by gavage). We used immunohistochemistry, electrophoretic mobility shift assays, and reverse transcription-polymerase chain reaction techniques. Compared with control dTGR, dTGR treated with cerivastatin had reduced mortality, blood pressure, cardiac hypertrophy, macrophage infiltration, and collagen I, laminin, and fibronectin deposition. Basic fibroblast growth factor mRNA and protein expression were markedly reduced, as was interleukin-6 expression. The transcription factors NF-kappaB and AP-1 were substantially less activated, although plasma cholesterol was not decreased.

CONCLUSIONS:

These results suggest that statins ameliorate Ang II-induced hypertension, cardiac hypertrophy, fibrosis, and remodeling independently of cholesterol reduction. Although the clinical significance remains uncertain, the results suggest that statins interfere with Ang II-induced signaling and transcription factor activation, thereby ameliorating end-organ damage.

• Authors: R Dechend, A Fiebeler, J K Park, D N Muller, J Theuer, E Mervaala, M Bieringer, D Gulba, R Dietz, F C Luft, H Haller
• Journal: Circulation (Circulation) Vol. 104 Issue 5 Pg. 576-81 (Jul 31 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11479256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD4 Antigens
• CD8 Antigens
• Fibronectins
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Interleukin-6
• NF-kappa B
• Oligonucleotides
• Pyridines
• RNA, Messenger
• Transcription Factor AP-1
• Fibroblast Growth Factor 2
• Angiotensinogen
• Angiotensin II
• Collagen
• cerivastatin
• Renin

Topics

• Angiotensin II (metabolism)
• Angiotensinogen (genetics, metabolism)
• Animals
• Animals, Genetically Modified
• Blood Pressure (drug effects)
• CD4 Antigens (analysis)
• CD8 Antigens (analysis)
• Cardiovascular Diseases (metabolism, mortality, prevention & control)
• Collagen (analysis)
• Fibroblast Growth Factor 2 (genetics)
• Fibronectins (analysis)
• Gene Expression Regulation (drug effects)
• Heart (drug effects, physiopathology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Immunohistochemistry
• Interleukin-6 (genetics)
• Male
• Myocardium (chemistry, metabolism, pathology)
• NF-kappa B (drug effects, metabolism)
• Oligonucleotides (metabolism)
• Protein Binding
• Pyridines (pharmacology)
• RNA, Messenger (drug effects, genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Renin (genetics, metabolism)
• Survival Analysis
• Survival Rate
• Transcription Factor AP-1 (drug effects, metabolism)