Effect of adenosine monophosphate‐activated protein kinase–p53–Krüppel‐like factor 2a pathway in hyperglycemia‐induced cardiac remodeling in adult zebrafish

Abstract

Aims/Introduction Diabetic cardiomyopathy is a type of myocardial disease. It causes left ventricular hypertrophy, followed by diastolic and systolic dysfunction, eventually leading to congestive heart failure. However, the underlying mechanism still requires further elucidation. Materials and Methods A high‐glucose zebrafish model was constructed by administering streptozocin intraperitoneally to enhance the development of cardiomyopathy and then treated with adenosine monophosphate‐activated protein kinase (AMPK) activator. Cardiac structure and function, and protein and gene expression were then analyzed. Cardiomyocytes (CMs) culture in vitro using lentivirus were used for detection of AMPK, p53 and Krüppel‐like factor 2a (klf2a) gene expression. Results In the hyperglycemia group, electrocardiogram findings showed arrhythmia, echocardiography results showed heart enlargement and dysfunction, and many differences, such as increased apoptosis and myocardial fiber loss, were observed. The phospho‐AMPK and klf2a expression were downregulated, and p53 expression was upregulated. Activation of phospho‐AMPK reduced p53 and increased klf2a expression, alleviated apoptosis in CMs and improved cardiac function in the hyperglycemic zebrafish. In vitro knockdown system of AMPK, p53 and klf2a using lentivirus illustrated an increased p53 expression and decreased klf2a expression in CMs by inhibiting AMPK. Repression of p53 and upregulation of klf2a expression were observed, but no changes in the expression of AMPK and its phosphorylated type. Conclusions In the model of streptozocin‐induced hyperglycemia zebrafish, the reduction of phosphorylated AMPK increased p53, which led to KLF2a decrease to facilitate apoptosis of CMs, inducing the cardiac remodeling and cardiac dysfunction. These results can be reversed by AMPK activator, which means the AMPK–p53–klf2a pathway might be a potential target for diabetic cardiomyopathy intervention.

Zebrafish Heart Failure Models

“…A hyperglycemia-induced model of diabetic CM in adult zebrafish induces cardiac hypertrophy and impaired diastolic function followed by impaired systolic function ( Sun et al, 2017 ). In another diabetic CM model, hyperglycemia is induced by intraperitoneal streptozocin injections, leading to heart enlargement, arrhythmias, and diastolic dysfunction followed by systolic dysfunction ( Wang et al, 2020 ). These models are relevant for investigating diabetic CM and HF.…”

Zebrafish as a Model for Cardiovascular and Metabolic Disease: The Future of Precision Medicine

“…Zebrafish metabolism research has advanced slowly compared to the cardiovascular discipline due to these and other factors. Table 4 presents some of the established metabolic disorder models: acute hyperglycemia [ 131 , 132 , 133 , 134 ], chronic hyperglycemia [ 133 , 134 , 135 , 136 , 137 , 138 ], genetically induced [ 139 , 140 , 141 ], and obesity [ 142 , 143 , 144 ]. We discuss select zebrafish-based metabolic disease models below.…”

Krüpple-like factors in cardiomyopathy: emerging player and therapeutic opportunities

“…It has been reported that KLF2a exerts cardio-protective effects through the AMPK-p53-KLF2a pathway. In a Streptozocin (STZ)-induced hyperglycemic zebrafish model, Wang et al ( 61 ) found that decreasing phosphorylated AMPK elevated p53, leading to KLF2a downregulation, which in turn, promoted cardiomyocyte apoptosis and induced cardiac remodeling and dysfunction. KLF10 participates in the regulation of various aspects of tissue homeostasis and cellular functions, including proliferation, differentiation, and apoptosis ( 155 , 156 ).…”