title: 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.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: W B
authors.initials: WB
authors.lastname: Zhang
authors.forename: Q J
authors.initials: QJ
authors.lastname: Du
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: A J
authors.initials: AJ
authors.lastname: Sun
authors.forename: Z H
authors.initials: ZH
authors.lastname: Qiu
authors.forename: C N
authors.initials: CN
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Zhao
authors.forename: H
authors.initials: H
authors.lastname: Gong
authors.forename: K
authors.initials: K
authors.lastname: Hu
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Zou
authors.forename: J B
authors.initials: JB
authors.lastname: Ge
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D005355:Fibrosis; D005464:Fluorobenzenes / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006984:Hypertrophy / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D000077022:Survivin; D020257:Ventricular Remodeling / Q000187:drug effects*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D053148:Caspase 3; D005464:Fluorobenzenes; D051858:Forkhead Transcription Factors; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D011743:Pyrimidines; D011945:Receptors, Angiotensin; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; D000077022:Survivin; D051025:bcl-Associated Death Protein; C494821:Bad protein, rat; C516989:Birc5 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C505410:Casp3 protein, rat