Characterisation of the cardiac function of synaptopodin 2-like protein (CHAP)

Cardiovascular disease development and heart failure are associated with various molecular alterations in the heart. One of the numerous altered but yet not fully characterized proteins is synaptopodin 2-like protein (Cytoskeletal Heart-enriched Actin-associated Protein CHAP). The protein belongs to the Z-disc proteins. It has been shown to be involved in the cardiac and skeletal muscle development and being associated with atrial fibrillation. Mice models of experimental heart failure showed higher CHAP expression. CHAP overexpressing transgenic mice displayed cardiac hypertrophy and fibrosis and it was concluded that the fetal form of the protein initiated progression to diastolic dysfunction. In line with these findings we observed increased protein level in cardiac tissue of patients with dilated cardiomyopathy (DCM) in comparison to controls. However, we estimated high abundance of CHAP protein already in heart biopsies of subjects with normal heart function. This suggests that the protein increase upon cardiac stress can also be involved in rather protective adaptations and that the protein as a potential therapeutic target should be investigated in more detail. We thus propose here to characterize the protein level and phosphorylation pattern upon physiological and pathophysiological conditions in patient samples and murine heart failure models. In collaboration with Prof. Frank (Kiel) we would like to investigate the impact of modulated CHAP protein levels on the cardiomyocyte’s response to biomechanical stress and identify the molecular alterations in NRVCM (neonatal rat ventricular cardiomyocytes) upon cyclic stretch. Characterization of CHAP in more detail will decipher the underlying mechanisms how the protein effect cardiac pathophysiology, possibly leading to various therapeutic approaches to prevent, halt or reverse pathologic disease progression.