title: Rosuvastatin-attenuated heart failure in aged spontaneously hypertensive rats via PKCα/β2 signal pathway.
abstract: There are controversies concerning the capacity of Rosuvastatin to attenuate heart failure in end-stage hypertension. The aim of the study was to show whether the Rosuvastatin might be effective or not for the heart failure treatment. Twenty-one spontaneously hypertensive rats (SHRs) aged 52 weeks with heart failure were randomly divided into three groups: two receiving Rosuvastatin at 20 and 40 mg/kg/day, respectively, and the third, placebo for comparison with seven Wistar-Kyoto rats (WKYs) as controls. After an 8-week treatment, the systolic blood pressure (SBP) and echocardiographic features were evaluated; mRNA level of B-type natriuretic peptide (BNP) and plasma NT-proBNP concentration were measured; the heart tissues were observed under electron microscope (EM); myocardial sarcoplasmic reticulum Ca(2+) pump (SERCA-2) activity and mitochondria cytochrome C oxidase (CCO) activity were measured; the expressions of SERCA-2a, phospholamban (PLB), ryanodine receptor2 (RyR2), sodium-calcium exchanger 1 (NCX1), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase inhibitor-1 (PPI-1) were detected by Western blot and RT-qPCR; and the total and phosphorylation of protein kinase Cα/β (PKCα/β) were measured. Aged SHRs with heart failure was characterized by significantly decreased left ventricular ejection fraction and left ventricular fraction shortening, enhanced left ventricular end-diastolic diameter and LV Volume, accompanied by increased plasma NT-proBNP and elevated BNP gene expression. Damaged myofibrils, vacuolated mitochondria and swollen sarcoplasmic reticulum were observed by EM. Myocardium mitochondria CCO and SERCA-2 activity decreased. The expressions of PLB and NCX1 increased significantly with up-regulation of PPI-1 and down-regulation of CaMKII, whereas that of RyR2 decreased. Rosuvastatin was found to ameliorate the heart failure in aged SHRs and to improve changes in SERCA-2a, PLB, RyR2, NCX1, CaMKII and PPI-1; PKCα/β2 signal pathway to be suppressed; the protective effect of Rosuvastatin to be dose dependent. In conclusion, the heart failure of aged SHRs that was developed during the end stage of hypertension could be ameliorated by Rosuvastatin.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases of Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Qiu
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhang
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Chaoneng
authors.initials: C
authors.lastname: Wu
authors.forename: Yong
authors.initials: Y
authors.lastname: Ye
authors.forename: Qijun
authors.initials: Q
authors.lastname: Du
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaona
authors.initials: X
authors.lastname: Hu
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Bao
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000375:Aging; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis; D015536:Down-Regulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D005464:Fluorobenzenes / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy*; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009210:Myofibrils / Q000187:drug effects / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000235:genetics; D010446:Peptide Fragments / Q000097:blood; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000068718:Rosuvastatin Calcium; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis; D013318:Stroke Volume / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003576:Electron Transport Complex IV; D005464:Fluorobenzenes; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D011506:Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D000068718:Rosuvastatin Calcium; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D013449:Sulfonamides; D000099211:Phospholamban; C506948:Atp2a2 protein, rat; C109794:pro-brain natriuretic peptide (1-76); C472592:protein phosphatase inhibitor-1, rat; C110374:sodium-calcium exchanger 1