Role of hemicentin-2 in myocarditis

• Applicant: Professorin Sophie van Linthout, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545262870

Myocarditis, an inflammatory cardiac disorder mostly caused by viral infections, is still a disorder with a poor prognosis. Clinical success of anti-inflammatory/immunomodulatory therapies in myocarditis and inflammatory cardiomyopathy are still limited, indicating the need for improved understanding of the crosstalk between inflammation and cardiac maladaptive remodeling, and the need for advanced regenerative approaches. We recently demonstrated that the anti-inflammatory drug, colchicine, reduced the progression of experimental Coxsackievirus B3 (CVB3) myocarditis. Subsequent evaluation of the impact of colchicine on the extracellular matrix (ECM) via label-free proteomic characterization on decellularized left ventricles revealed that ECM proteins were regulated in the left ventricle following colchicine application in CVB3 mice. In particular, hemicentin-2 (HMCN-2), belonging to the fibulin family was increased in CVB3 mice following colchicine treatment. Based on 1) our in vivo findings, showing regulation of the ECM protein HMCN-2, which has not previously been studied in relation to the heart, inflammatory cardiomyopathy or heart failure, 2) our subsequent in vitro data indicating an involvement of HMCN-2 in the modulation of fibroblast activation and collagen deposition, 3) the growing appreciation that an interrelation exists between ECM and immune cells, and 4) our patient data illustrating lower HMCN-2 mRNA expression in endomyocardial biopsies of myocarditis versus control patients (conform to our in vivo data), we aim to get insights into the role of HMCN-2 in cardiac remodeling and inflammation in myocarditis/inflammatory cardiomyopathy. In detail, we aim 1) to evaluate the impact of HMCN-2 on the ECM-modulating and inflammatory potential of cardiac fibroblasts; 2) to evaluate the impact of HMCN-2 on cardiac remodeling and inflammation in experimental CVB3-induced myocarditis mice, and 3) to evaluate the expression of HMCN-2 in endomyocardial biopsies and serum of myocarditis, inflammatory cardiomyopathy and dilated cardiomyopathy patients.

• DFG Programme: Research Grants