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Rosuvastatin-attenuated heart failure in aged spontaneously hypertensive rats via PKCα/β2 signal pathway
Zhaohui Qiu1, Wenbin Zhang, Fan Fan
1Shanghai Institute of Cardiovascular Diseases of Zhongshan Hospital, Fudan University, Shanghai, China.
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.
Insights
Rosuvastatin effectively treats heart failure in aged hypertensive rats by improving cardiac function and molecular markers. The drug
Area of Science:
- Cardiology
- Pharmacology
Background:
- Hypertension-induced heart failure is a significant clinical concern.
- The efficacy of statins, specifically Rosuvastatin, in treating advanced heart failure in hypertensive models remains debated.
Purpose of the Study:
- To investigate the therapeutic potential of Rosuvastatin in ameliorating heart failure in spontaneously hypertensive rats (SHRs).
- To elucidate the underlying molecular mechanisms of Rosuvastatin's action on cardiac function and structure.
Main Methods:
- Aged SHRs with established heart failure were treated with varying doses of Rosuvastatin or placebo for 8 weeks.
- Evaluations included systolic blood pressure, echocardiography, cardiac biomarker analysis (BNP, NT-proBNP), electron microscopy, and molecular assessments (Western blot, RT-qPCR) of key proteins.
Main Results:
- Rosuvastatin treatment significantly improved cardiac function, evidenced by enhanced ejection fraction and fractional shortening.
- Molecular analysis revealed that Rosuvastatin modulated the expression and activity of proteins involved in calcium handling (SERCA-2a, PLB, RyR2, NCX1) and signaling pathways (CaMKII, PPI-1, PKCα/β).
- The protective effects were dose-dependent, with observed improvements in cardiac structure and reduced pathological markers.
Conclusions:
- Rosuvastatin demonstrates a significant ameliorative effect on end-stage hypertensive heart failure in aged SHRs.
- The drug's benefits are linked to the restoration of calcium handling proteins and the suppression of specific signaling pathways.
- These findings support Rosuvastatin's potential as a therapeutic agent for heart failure in hypertensive conditions.
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