Mechanisms of acute CD40-mediated damage in cardiac ischemia

• Applicant: Professor Dr. Norbert Gerdes
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569468610

Background and previous work: Co-stimulatory signals modify responses of the immune system towards tissue insult or injury. Expression and function of CD40/CD40 ligand (L), a prominent representative dyad of co-stimulatory molecules, is elevated in patients with diabetes mellitus (DM) and is substantially linked with mortality. However, the role of the CD40/CD40L axis in acute tissue injury in myocardial infarction (AMI) is unclear. We demonstrated that inhibiting CD40-TRAF6 signaling, the major CD40 signaling pathway in monocytes and macrophages, during the acute phase of ischemia/reperfusion (I/R) injury had no benefit. In contrast, activation of CD40 with an agonistic antibody (clone FGK45; commencing before or after I/R) resulted in significantly impaired left ventricular function coinciding with increased infarct size and changed cardiac immune cells 24 hours of I/R. Enhanced CD40L expression and ensuing CD40 signaling is crucial in obesity-related metabolic dysregulation and delivers a poor prognosis for AMI patients. Aims: We will investigate how elevated CD40L in DM contributes to activation of CD40 signaling, effector cell activation, and increased acute damage in myocardial I/R. WP1: Cell types and effector mechanisms of CD40-mediated acute I/R injury Cell types expressing CD40 (receptor) responsible for CD40-mediated cardiac damage will be investigated. Subsequently, we will reveal the relevant signaling and effector mechanism responsible for aggravated myocardial damage and dysfunction following I/R under CD40 stimulation. WP2: Sources of elevated CD40L in I/R and diabetes We will examine the presumably potentiated expression of CD40L in models of DM. Cell type-specific gene deletion and pharmacologic blockade of CD40L in dysmetabolic I/R will identify relevant cell types and gauge therapeutic potential. WP3: Regulation of CD40L in patients with diabetes and AMI. We will analyze CD40L expression in patients with cardiovascular disease and evaluate the predictive value of CD40L as a potential biomarker in AMI with and without DM. Significance: The proposed research program will highlight the relevance of CD40 signaling in the acute damage processes in AMI, especially under comorbid conditions such as diabetes mellitus.

• DFG Programme: Research Grants