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Growth Inhibitory Signaling of the Raf/MEK/ERK Pathway

The MEK/ERK Module Is Reprogrammed in Remodeling Adult Cardiomyocytes

Department of Cardiac Surgery, Kerckhoff Heart Center, Benekestrasse 2-8, 61231 Bad Nauheim, Germany
Campus Kerckhoff, Justus-Liebig-University Giessen, 61231 Bad Nauheim, Germany
Institute for Pharmacology and Preventive Medicine, Bahnhofstraße 20, 49661 Cloppenburg, Germany
Pediatric Heart Center, Justus Liebig University, Feulgenstrasse 10-12, 35392 Giessen, Germany
Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, 60590 Frankfurt/Main, Germany
Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 84104 Bratislava, Slovakia
Authors to whom correspondence should be addressed.
Authors contributed equally.
Int. J. Mol. Sci. 2020, 21(17), 6348;
Received: 30 June 2020 / Revised: 26 August 2020 / Accepted: 30 August 2020 / Published: 1 September 2020
(This article belongs to the Special Issue MAPK-ERK Pathway)
Fetal and hypertrophic remodeling are hallmarks of cardiac restructuring leading chronically to heart failure. Since the Ras/Raf/MEK/ERK cascade (MAPK) is involved in the development of heart failure, we hypothesized, first, that fetal remodeling is different from hypertrophy and, second, that remodeling of the MAPK occurs. To test our hypothesis, we analyzed models of cultured adult rat cardiomyocytes as well as investigated myocytes in the failing human myocardium by western blot and confocal microscopy. Fetal remodeling was induced through endothelial morphogens and monitored by the reexpression of Acta2, Actn1, and Actb. Serum-induced hypertrophy was determined by increased surface size and protein content of cardiomyocytes. Serum and morphogens caused reprogramming of Ras/Raf/MEK/ERK. In both models H-Ras, N-Ras, Rap2, B- and C-Raf, MEK1/2 as well as ERK1/2 increased while K-Ras was downregulated. Atrophy, MAPK-dependent ischemic resistance, loss of A-Raf, and reexpression of Rap1 and Erk3 highlighted fetal remodeling, while A-Raf accumulation marked hypertrophy. The knock-down of B-Raf by siRNA reduced MAPK activation and fetal reprogramming. In conclusion, we demonstrate that fetal and hypertrophic remodeling are independent processes and involve reprogramming of the MAPK. View Full-Text
Keywords: Ras; Rap; Raf; MEK; ERK; remodeling; reprogramming; dedifferentiation; hypertrophy; heart failure Ras; Rap; Raf; MEK; ERK; remodeling; reprogramming; dedifferentiation; hypertrophy; heart failure
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MDPI and ACS Style

Kubin, T.; Cetinkaya, A.; Kubin, N.; Bramlage, P.; Sen-Hild, B.; Gajawada, P.; Akintürk, H.; Schönburg, M.; Schaper, W.; Choi, Y.-H.; Barancik, M.; Richter, M. The MEK/ERK Module Is Reprogrammed in Remodeling Adult Cardiomyocytes. Int. J. Mol. Sci. 2020, 21, 6348.

AMA Style

Kubin T, Cetinkaya A, Kubin N, Bramlage P, Sen-Hild B, Gajawada P, Akintürk H, Schönburg M, Schaper W, Choi Y-H, Barancik M, Richter M. The MEK/ERK Module Is Reprogrammed in Remodeling Adult Cardiomyocytes. International Journal of Molecular Sciences. 2020; 21(17):6348.

Chicago/Turabian Style

Kubin, Thomas, Ayse Cetinkaya, Natalia Kubin, Peter Bramlage, Bedriye Sen-Hild, Praveen Gajawada, Hakan Akintürk, Markus Schönburg, Wolfgang Schaper, Yeong-Hoon Choi, Miroslav Barancik, and Manfred Richter. 2020. "The MEK/ERK Module Is Reprogrammed in Remodeling Adult Cardiomyocytes" International Journal of Molecular Sciences 21, no. 17: 6348.

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