急性心肌梗塞相關心臟衰竭小鼠模型之利尿鈉肽基因療法研究

Abstract

研究背景：心臟衰竭是指心臟無法有效地泵送血液，通常由冠狀動脈疾病或慢性缺血性心臟病導致所引起。在心臟衰竭中，心臟會產生更多的利尿鈉肽，有助於透過促進利尿作用和心室重塑來減輕症狀及回復心臟功能。儘管基因治療在其他疾病中已有成功的例子，但在心臟衰竭後心肌梗塞的利尿鈉肽基因治療尚未有明確之方針。本研究旨在探討腦利尿鈉肽基因治療在由左前降支動脈結紮誘導的小鼠心臟衰竭模型中的療效，以尋找新的潛在治療策略。 方法：將32隻C57BL/6小鼠隨機分為三組：對照組、僅冠狀動脈結紮組和冠狀動脈結紮組與質粒-腦利尿鈉肽基因治療組。利用pCMV6-Entry載體傳遞腦利尿鈉肽的Nppb基因，並附有Myc-DDK標籤。小鼠心臟超音波於手術後4週及8週施作用以評估心臟功能，並進行組織學評估以檢測心肌損傷及重塑情況。 結果：心臟超音波評估顯示，與僅冠狀動脈結紮組相比，基因治療組在心臟功能方面顯著改善，包括較高的左心室射出分率（ejection fraction）、短縮分率（Fractional shortening）和舒張期心室間隔厚度（Interventricular septal thickness）。而在左心室舒張末期容積 (ventricular end-diastolic volume)，雖然結果並不顯著，但基因治療組相較僅結紮組呈現下降趨勢。而在組織學的檢查，顯示基因治療組中心肌肥大和纖維化減少。基因治療組中的VEGF表現上升，心肌細胞修復能力增強，而Caspase-3的表現在各組中沒有顯著差異。 結論：本研究成果展示了利尿鈉肽基因治療顯著減少冠狀動脈結紮後引起之心臟衰竭及心肌損傷，提供心肌梗塞後引發心臟衰竭的一種潛在治療策略。

Background: Heart failure (HF) occurs when the heart cannot pump blood effectively, often due to coronary artery disease from myocardial infarction (MI) or chronic ischemic dysfunction. In HF, the heart produces more brain natriuretic peptide (BNP), which helps reduce symptoms by promoting natriuresis and aiding ventricular remodeling. Despite the success of gene therapy in other diseases, its use targeting natriuretic peptides for HF post-MI remains unexplored. This study investigates the efficacy of BNP gene therapy in a mouse model of HF induced by left anterior descending artery (LAD) ligation, simulating MI, to offer a potential new treatment strategy.

Methods: Thirty-two C57BL/6 mice were assigned to three groups: control, LAD ligation-only, and LAD ligation with plasmid-BNP gene therapy. The Nppb gene, encoding brain natriuretic peptide (BNP), was delivered using a pCMV6-Entry vector with a Myc-DDK tag. Cardiac function was evaluated via echocardiography at 4- and 8-weeks post-surgery, alongside histological assessments to gauge myocardial damage and remodeling.

Results: Echocardiographic evaluation revealed significant improvements in the gene therapy group compared to the LAD ligation-only group, including higher ejection fraction (EF), fractional shortening (FS) and interventricular septal thickness in diastole (IVSd). The left ventricular end-diastolic volume showed a non-significant decreasing trend. Histological findings indicated reduced cardiac hypertrophy and fibrosis in the gene therapy group. VEGF expression was elevated in the gene therapy group, suggesting enhanced cardiomyocyte repair, while Caspase-3 levels were consistent across all groups.

Conclusions: Gene therapy using natriuretic peptides may significantly ameliorate cardiac dysfunction in HF induced by LAD ligation. This result may pave the way for future innovative post-MI HF treatments.