Ultrasound-targeted microbubble technology facilitates SAHH gene delivery to treat diabetic cardiomyopathy by activating AMPK pathway

Xiaohui Guo; Kegong Chen; Lin Ji; Shanjie Wang; Xiangmei Ye; Liang Xu; Leiguang Feng

doi:10.1016/j.isci.2024.108852

Ultrasound-targeted microbubble technology facilitates SAHH gene delivery to treat diabetic cardiomyopathy by activating AMPK pathway

iScience. 2024 Jan 11;27(2):108852. doi: 10.1016/j.isci.2024.108852. eCollection 2024 Feb 16.

Authors

Xiaohui Guo^{1

2}, Kegong Chen³, Lin Ji⁴, Shanjie Wang², Xiangmei Ye¹, Liang Xu⁵, Leiguang Feng¹

Affiliations

¹ Department of Clinical Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin 150081, P.R. China.
² The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin 150086, P.R. China.
³ Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, P.R. China.
⁴ Department of Orthopedics, The First Hospital of Harbin, Harbin 150010, P.R. China.
⁵ Department of Cardiology, The Second Hospital of Harbin, Harbin 150056, P.R. China.

Abstract

Diabetic cardiomyopathy (DCM) is a cardiovascular complication with no known cure. In this study, we evaluated the combination of ultrasound-targeted microbubble destruction (UTMD) and cationic microbubbles (CMBs) for cardiac S-adenosyl homocysteine hydrolase (SAHH) gene transfection as potential DCM therapy. Models of high glucose/fat (HG/HF)-induced H9C2 cells and streptozotocin-induced DCM rats were established. Ultrasound-mediated SAHH delivery using CMBs was a safe and noninvasive approach for spatially localized drug administration both in vitro and in vivo. Notably, SAHH overexpression increased cell viability and antioxidative stress and inhibited apoptosis of HG/HF-induced H9C2 cells. Likewise, UTMD-mediated SAHH delivery attenuated apoptosis, oxidative stress, cardiac fibrosis, and myocardial dysfunction in DCM rats. Activation of the AMPK/FOXO3/SIRT3 signaling pathway may be a key mechanism mediating the role of SAHH in regulating myocardial injury. Thus, UTMD-mediated SAHH transfection may be an important advancement in cardiac gene therapy for restoring ventricular function after DCM.

Keywords: Biological sciences; Biotechnology; Cardiovascular medicine; Molecular biology.