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Ameliorated stress related proteins are associated with improved cardiac function by sarcoplasmic reticulum calcium atpase gene transfer in heart failure

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Journal of Geriatric Cardiology 2012年第3期9卷 269-277页

作者： Zhi-Qing Fu Xiao-Ying Li Xiao-Chun Lu Ya-Fei Mi Tao Liu Wei-Hua Ye First Department of Geriatric Cardiology Chinese PLA General Hospital 28 Fuxing Road Beijing 100853 China Department of Geriatric Ultrasound Chinese PLA General Hospital 28 Fuxing Road Beijing 100853 China Department of Cardiac Surgery Chinese PLA General Hospital 28 Fuxing Road Beijing 100853 China

Background Previous studies showed that overexpression of sarco-endoplasmic retieulum calcium atpase （SERCA2a） in a variety of heart failure （HF） models was associated with greatly enhanced cardiac performance. However, it still undefined the effect of SERCA2a overexpression on the systemic inflammatory response and neuro-hormonal factors. Methods A rapid right ventricular pacing model of experimental HF was used in beagles. Then the animals underwent recombinant adeno-associated vires 1 （rAAV1） mediated gene trans- fection by direct intra-myocardium injection. HF animals were randomized to receive the SERCA2a gene, enhanced green fluorescent protein （control） gene, or equivalent phosphate buffered saline. Thirty days after gene delivery, the cardiac function was evaluated by echocardiographic testing. The protein level of SERCA2a was measured by western blotting. The proteomic analysis of left ventricular （LV） sample was determined using two-dimensional （2-D） gel el^ctrophoresis and MALDI-TOF-MS. The serum levels of the systemic inflammatory and neuro-hormonal factors were assayed using radioimmunoassay kits. Results The cardiac function improved after SERCA- 2a gene transfer due to the significantly increased SERCA2a protein level. Beagles treated with SERCA2a had significantly decreased serum levels of the inflammatory markers （interleukin-6 and tumor necrosis factor-a） and neuro-hormonal factors （brain natriuretic peptide, endothelin-1 and angiotensin II） compared with HF animals. The myocardial proteomic analysis showed that haptoglobin heavy chain, heat shock protein （alpha-crystallin-related, B6） were down-regulated, and galectin-1 was up-regulated in SERCA2a group compared with HF group, companied by up-regulated contractile proteins and NADH dehydrogenase. Conclusions These findings demonstrate that regional intramyocardial injections of rAAV 1-SERCA2a vectors may improve global LV function, correlating with reverse activation of the systemic inflammatory,

关键词： Heart failure sarco-endoplasmic reticulum calcium atpase Gene transfer Stress reaction Neuro-hormonal factors

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Improvement in cardiac function after sarcoplasmic reticulum Ca^2＋-atpase gene transfer in a beagle heart failure model

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Chinese Medical Journal 2009年第12期122卷 1423-1428页

作者： MI Ya-fei LI Xiao-ying TANG Li-jiang LU Xiao-chun FU Zhi-qing YE Wei-hua Department of Cardiology Taizhou Hospital of Zhejiang Province Wenzhou Medical College Linhai Zhejiang 317000 China Department of Geriatric Cardiology Chinese PLA General Hospital Beijing 100853 China Department of Cardiac Surgery Chinese PLA General Hospital Beijing 100853 China

Background Heart failure （HF） is a major cause of morbidity and mortality worldwide, but current treatment modalities cannot reverse the underlying pathological state of the heart. Gene-based therapies are emerging as promising therapeutic modalities in HF patients. Our previous studies have shown that recombinant adeno-associated viral （rAAV） gene transfer of sarco-endoplasmic reticulum calcium atpase （SERCA2a） can be effective in treating rats with chronic heart failure （CHF）. The aim of this study was to examine the effects of SERCA2a gene transfer in a large HF animal model. Methods HF was induced in beagles by rapid right ventricular pacing （230 beats/min） for 30 days. A reduced rate ventricular pacing （180 beats/min） was continued for another 30 days. The beagles were assigned to four groups：（a） control group （n=4）; （b） HF group （n=4）; （c） enhanced green fluorescent protein group （n=4）; and （d） SERCA2a group （n=4）. rAAV1-EGFP （1×10^12 μg） and rAAV1-SERCA2a （1×10^12 μg） were delivered intramyocardially. SERCA2a expression was assessed by Western blotting and immunohistochemistry. Results Following 30 days of SERCA2a gene transfer in HF beagles its protein expression was significantly higher than in the HF group than in the control group （P 〈0.05）. Heart function improved along with the increase in SERCA2a expression. Left ventricular systolic function significantly improved, including the ejection fraction, left ventricular systolic pressure, maximal rate of rise of left ventricular pressure （＋dp/dtmax）, and the maximal rate of decline of left ventricular pressure （-dp/dtmax）（P 〈0.05）. Left ventricular end-diastole pressure significantly decreased （P 〈0.05）. The expression of SERCA2a in the myocardial tissue was higher in the SERCA2a group than in the HF group （P〈0.05）. Conclusions Intramyocardial injection of rAAV1-SERCA2a can improve the cardiac function in beagles induced with HE We expect further studies on SERCA2a＇s long-term safety, efficacy, dosage and

关键词： heart failure gene therapy sarco-endoplasmic reticulum calcium atpase

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