Investigating the mechanisms of SGTL2i and GLP1 receptor agonists in cellular models of diabetic cardiomyopathy

Clinical observations underline the tight correlation of heart failure (HF) and diabetes. Recent outcomes of clinical trials revealed cardioprotective effects of sodium glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) in type 2 diabetes (T2D) patients at risk for cardiovascular disease (CVD). Anti-fibrotic and anti-inflammatory effects for SGLT2i have been observed in cellular models with cardiac fibroblasts and cardiomyocytes. Treatment with GLP1-RA has been shown to reduce infarct size and inflammatory markers after myocardial infarction. Although direct effects of SGLT2i and GLP1-RA were observed in animal models as well as in in vitro experiments, the expression of their respective targets in the myocardium are controversially discussed.

The aim of the current project is the investigation and comparison of the cardioprotective effects of GLP1-RA and SGLT2i in cardiac fibroblasts and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to explain the clinical findings and identify the molecular basis.

The design of a diabetic model of cardiac cell types will be chosen based on the results of current investigations on the establishment of a diabetic cardiomyopathy model using iPSC-CMs. First, induced pluripotent stem cells will be cultured and differentiated into cardiomyocytes. The expression of SGLT1, SGLT2, NHE-1 (sodium hydrogen exchanger 1) and GLP1R will be examined in iPSC-CMs cultured under low glucose- (7 mM) and high glucose conditions (22 - 30 mM) using qPCR und Western Blot. As shown in our previous experiments, the medium will be further modified with 10 nM endothelin-1 and 1 µM cortisone to induce phenotype of diabetic cardiomyopathy.

Cultivation of iPSC-CMs and cardiac fibroblasts under diabetic conditions will be performed under the treatment with SGLT2i (empagliflozin) and GLP1-RA (GLP-1, liraglutide). Cellular phenotype will be studied using immunostaining with cardiac- and fibroblast-specific markers. Functionality of iPSC-CMs will be documented by motion-based video analysis. Expression of marker genes for metabolic status (HK2, PDK4, CD36, GLUT1, GLUT4, CPT1B), inflammation (IL-6), hypertrophy and fibrosis (NPPB, COL1A1, COL3A1) of cardiomyocytes and fibroblasts will be examined using qPCR.