The therapeutic effect of rosuvastatin on cardiac remodelling from hypertrophy to fibrosis during the end-stage hypertension in rats.

Abstract

End-stage hypertensive heart disease is an increasing cause of cardiac mortality. Therefore, the current study focused on the cardiac remodelling from hypertrophy to fibrosis in old-aged spontaneously hypertensive rats (SHRs), and explored the therapeutic effects of Rosuvastatin and its possible mechanism(s) of action. Spontaneously hypertensive rats at age 52 weeks were randomly divided into three groups, the first two to receive Rosuvastatin at a dose of 20 mg/kg/day and 40 mg/kg/day, respectively, and the third to receive placebo, which was to be compared with Wistar-Kyoto as controls. After 2-month treatment, SBP, heart to body weight ratio (HW/BW%) and echocardiographic features were evaluated, followed by haematoxylin and eosin and Masson trichrome staining in conjunction with qPCR of foetal gene expressions. Transferase-mediated dUTP nick-end labelling assay and immunofluorescent labelling for active caspase-3 were used to detect the apoptotic cardiomyocytes. Signaling pathways involved were examined by using western blot. Old-aged SHR developed end-stage hypertensive heart disease characterized by significant enhancement of HW/BW%, LVAWd and LVPWd, and decreased LVEF and LVFS, accompanied by cardiomyocytes enlargement and fibrosis along with activation of foetal gene programme. Cardiac apoptosis increased significantly during the transition process. Rosuvastatin reduced hypertrophy significantly via AT(1) Receptor-PKCβ2/α-ERK-c-fos pathway; protected myocardium against apoptosis via Akt-FOXO1, Bcl-2 family and survivin pathways and consequently suppressed the caspase-3 activity. The present study revealed that old-aged SHRs developed cardiac remodelling from hypertrophy to fibrosis via cardiac apoptosis during the end stage of hypertensive heart disease. These pathological changes might be the consequence of activation of AT(1) Receptor-PKCβ2/α-ERK-c-fos and AKT-FOXO1/Bcl-2/survivin/Caspase3 signaling. Rosuvastatin effectively attenuated the structural changes by reversing the signaling transductions involved.

• Authors: W B Zhang, Q J Du, H Li, A J Sun, Z H Qiu, C N Wu, G Zhao, H Gong, K Hu, Y Z Zou, J B Ge
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 16 Issue 9 Pg. 2227-37 (Sep 2012) ISSN: 1582-4934 [Electronic] England
• PMID: 22288611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Bad protein, rat
• Birc5 protein, rat
• Fluorobenzenes
• Forkhead Transcription Factors
• Microtubule-Associated Proteins
• Nerve Tissue Proteins
• Pyrimidines
• Receptors, Angiotensin
• Sulfonamides
• Survivin
• bcl-Associated Death Protein
• Foxo1 protein, rat
• Rosuvastatin Calcium
• Protein Kinase C
• Protein Kinase C beta
• Casp3 protein, rat
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Fibrosis
• Fluorobenzenes (pharmacology)
• Forkhead Transcription Factors (metabolism)
• Hypertension (complications, drug therapy, pathology)
• Hypertrophy (complications, drug therapy, pathology)
• Male
• Microtubule-Associated Proteins (metabolism)
• Myocytes, Cardiac (drug effects, pathology)
• Nerve Tissue Proteins (metabolism)
• Protein Kinase C (metabolism)
• Protein Kinase C beta
• Pyrimidines (pharmacology)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Receptors, Angiotensin (metabolism)
• Rosuvastatin Calcium
• Signal Transduction
• Sulfonamides (pharmacology)
• Survivin
• Ventricular Remodeling (drug effects)
• bcl-Associated Death Protein (metabolism)