S100A4: Evaluation eines neuen Kandidatenproteins für die Prävention kardialen Zelltods und Steigerung der Regenerationsfähigkeit im ischämischen Myokard
Final Report Abstract
The applicant has worked on two major projects during the reported period. Initial breeding and maintaining of the S100A4-/- mice was challenging, therefore the initial focus was to finish the PRAS40 study. PRAS40 was initially identified as a 14-3-3 binding protein15 and was subsequently identified as an mTORC1 inhibitor10,11. mTORC1 inhibition with rapamycin has been shown to prevent remodeling and improve function in cardiac diseases. However off target and systemic effects prevent a general use in cardiac disease states. Current therapeutic approaches also fail to differentially regulate mTORC1 vs. mTORC2. Proline Rich AKT Substrate of 40kDa (PRAS40) inhibits only mTORC1 activity, but the role of PRAS40 in myocytes has been overlooked. We found that PRAS40 overexpression using a clinically relevant adeno-associated (AAV9) gene transfer blocks mTORC1 in cardiomyocytes, blunts pathological remodeling after pressure overload, and preserves cardiac function. PRAS40 mediated mTORC1 inhibition boosts mTORC2 signaling and thereby protects the myocardium against ischemic injury in vivo. Disruption of AKT signaling in vivo diminishes the protective effect of PRAS40. PRAS40 represents a prominent tool to prevent pathological remodeling by inhibition of mTORC1 in diseased myocardium, while simultaneously promoting protective mTORC2 function. In addition, the applicant characterized the role of S100A4 protein during heart development and after myocardial infarction. S100 proteins belongs to the EF-hand Ca2+-binding protein family that regulates several biological activities, such as proliferation, migration and cell differentiation. No information exists whether functional consequences of increased or decreased S100A4 protein levels in injured myocardium bear beneficial or detrimental effects. Existing data indicate that S100A4 promotes cardiomyogenesis and induces differentiation and proliferation of stem cells. S100A4 is highly expressed in embryonic hearts and in interstitial myocardial cells. Global deletion of S100A4 in S100A4-/- mice resulted in dilated cardiomyopathy at one year of age and decreased cardiac function after myocardial infarction compared to control mice. Current research will focus to identify the underlying molecular mechanisms. In contrast, AAV9 mediated gene transfer of S100A4 in cardiomyocytes resulted in improved cardiac function after myocardial infarction, indicating that S100A4 indeed might be a cardioprotective factor. The causal relationship of S100A4 in reducing infarct size and remodeling is to be confirmed by ongoing in vivo and in vitro studies. Understanding the mechanism by which S100A4 protects myocardium might help to develop novel strategies to treat cardiac diseases.
Publications
- Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes. Journal of Molecular and Cellular Cardiology (February 10, 2010)
Voelkers M, Salz M, Herzog N, Frank D, Dolatabadi N, Frey N, Gude N, Friedrich O, Koch WJ, Katus HA, Sussman MA, Most P
- Pim-1 kinase protects mitochondrial integrity in cardiomyocytes. Circulation Research 106: 1265–1274, 2010
Borillo GA, Mason M, Quijada P, Völkers M, Cottage C, McGregor M, Din S, Fischer K, Gude N, Avitabile D, Barlow S, Alvarez R, Truffa S, Whittaker R, Glassy MS, Gustafsson AB, Miyamoto S, Glembotski CC, Gottlieb RA, Brown JH, Sussman MA
- Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosis. Eur. Heart J. 32: 2179–2188, 2011
Cheng Z, Völkers M, Din S, Avitabile D, Khan M, Gude N, Mohsin S, Bo T, Truffa S, Alvarez R, Mason M, Fischer KM, Konstandin MH, Zhang X-K, Heller Brown J, Sussman MA
- Myocardial AKT: the omnipresent nexus. Physiol. Rev. 91: 1023–1070, 2011
Sussman MA, Völkers M, Fischer K, Bailey B, Cottage CT, Din S, Gude N, Avitabile D, Alvarez R, Sundararaman B, Quijada P, Mason M, Konstandin MH, Malhowski A, Cheng Z, Khan M, McGregor M
- Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin. Proceedings of the National Academy of Sciences 108: 6145–6150, 2011
Avitabile D, Bailey B, Cottage CT, Sundararaman B, Joyo A, McGregor M, Gude N, Truffa S, Zarrabi A, Konstandin M, Khan M, Mohsin S, Völkers M, Toko H, Mason M, Cheng Z, Din S, Alvarez R, Fischer K, Sussman MA
- Pim-1 kinase inhibits pathological injury by promoting cardioprotective signaling. Journal of Molecular and Cellular Cardiology 51: 554–558, 2011
Fischer KM, Cottage CT, Konstandin MH, Völkers M, Khan M, Sussman MA
- Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish. J Cell Sci 125: 287–294, 2012
Völkers M, Dolatabadi N, Gude N, Most P, Sussman MA, Hassel D
(See online at https://doi.org/10.1242/jcs.090464)
