The role of the z-disc protein LMCD1 in cardiac remodeling.

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Cardiac hypertrophy is an integral part of the remodeling process the heart undergoes when subjected to biomechanical or neurohumoral stressors. Adaptive hypertrophy is typically a short-term and mostly reversible compensation to maintain cardiac function. However, when stressors persist, the hypertrophy might become maladaptive or pathological. On the cellular level, the development of pathological hypertrophy is hallmarked not only by cardiomyocyte growth but also by fibrosis, and apoptotic cell death. Typical stimuli of maladaptive remodeling are a prior myocardial infarction, hypertension, valvular heart disease, and certain mutations in cardiac proteins. Several signaling cascades are involved in these processes. The transition between adaptive and maladaptive hypertrophy and the signaling involved might be indistinct in some cases. Yet, in the context of pathological remodeling, the NFAT/calcineurin signaling pathway plays an important role. Main goal of the project is the in-depth in vivo characterization of the role of the protein LMCD1 in cardiac remodeling. In previous studies we could showthat LMCD1 is sufficient to induce Calcineurin-mediated cardiac hypertrophy in vivo. The focus now will be on the analyses of the effects of the downregulation of LMCD1 in vitro and in vivo. To pursue this task, we have newly generated a conditional LMCD1-“knockout”-mouse model. The following hypotheses will be addressed: a) Does the downregulation of LMCD1 affect the calcineurin-mediated hypertrophy in biomechanically stretched cardiomyocytes in vitro? b) Does the downregulation of LCMD1 in vivo beneficially modulate pathological hypertrophy induced by pressure overload or neurohumoral activation? Here, we will also utilize a strategy for an LMCD1 knockdown after the onset of the hypertrophic stimulus to test for potential therapeutic effects. c) Identification and characterization of mechanistically relevant novel players (genes/transcripts/non-coding RNAs) which play role in cardiac remodeling, in particular in the context of the LMCD1 “knockout”. We are also planning to include human blood samples from patients with severe symptomatic aortic stenosis in these analyses in order to identify circulating non-coding RNAs which might play a critical role in the mediation of pathological hypertrophy. These results might help not only to understand the mechanistic background of LMCD1 but may also to improve our in-depth understanding of maladaptive remodeling in general and trigger future experiments. Taken together, we are expecting to a identify a potentially prophylactic or even therapeutic effect for the downregulation of LMCD1 in vivo. Ultimately, these findings could lead to further translation towards a treatment for the negative effects of maladaptive remodeling.