Project Details
Projekt
Reduction of infarct size and improvement of cardiac function by functional and dysfunctional high-density lipoproteins (HDL) in coronary artery disease and diabetes: molecular mechanisms and therapeutic approaches
Subject Area
Cardiology, Angiology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 560579599
The mortality of individuals with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) is two- to fourfold higher compared to people with CAD alone. Dysfunction of High-density lipoproteins (HDL) is involved in the pathogenesis of both CAD and DM. We have observed that HDL isolated from CAD and DM patients and administered prior to acute myocardial infarction (AMI) in mice failed to protect the heart, whereas administration of HDL from healthy individuals was clearly cardioprotective. We hypothesized that this was due to the decreased concentrations of sphingosine-1-phosphate (S1P) we identified in CAD-HDL and DM-HDL (HDL-S1P), a bioactive lipid responsible for several beneficial effects of HDL including cardioprotection. Remarkably, therapeutic loading of CAD-HDL with exogenous S1P completely restored cardioprotection, whereas that of DM-HDL did not. In a second approach, we tested the hypothesis that not only dysfunctional DM-HDL may contribute to the worse clinical outcome of AMI in DM patients, but also that diabetic hearts may be less responsive to HDL-mediated cardioprotection per se. Indeed, we have observed that mice on a diet-induced obesity (DIO) diet were not only hyperglycemic, insulin-resistant and hyperinsulinemic but also completely resistant to cardioprotection by healthy HDL. Remarkably, this resistance extended to S1P administration itself. Therefore, we believe that it is of utmost importance to comprehend the reasons for DM-HDL’s ineffectiveness to exert cardioprotection, and to explore the mechanisms of the diabetic heart’s refractoriness to HDL-S1P-mediated cardioprotection. To characterize both defects and identify ways to overcome them thera¬peutically is the main focus of this project. Thus the main aims of this proposal are: (I) Identify and correct the molecular defects in CAD-HDL and DM-HDL that impede cardioprotection; (II) Identify the causes of the diabetic heart’s refractoriness to HDL-S1P cardioprotection in mice and humans, and (III) Design strategies to restore and improve endogenous HDL-S1P cardioprotection in CAD and DM. We will employ state of the art molecular, cell biological and genetic tools to dissect these pathways experimentally, and will translate them into interventional strategies. In summary, we believe that the identification and interventional boosting of any mechanism that enhances HDL-S1P’s cardioprotective efficiency will pave the road to novel therapies in patients at risk of AMI with and without DM.
DFG Programme
Research Grants
Major Instrumentation
High-Resolution Respirometer
Instrumentation Group
3560 Warburg-Apparaturen, Zellstoffwechsel-Analysengeräte
