Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Lmcd1-deficiency attenuates already early stages of maladaptive cardiac hypertrophy in vitro and in vivo

L. Kilian1, S. Martini1, N. Schmiedel1, J. Voran1, J. Richter1, O. J. Müller1, D. Frank1

1Med. Klinik III / Kardiologie, Angiologie, Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Kiel;

Heart failure and hypertensive heart disease were responsible for more than 58,400 deaths in Germany in 2020. Maladaptive hypertrophy is associated with hypertension and a mayor risk factor for the development of heart failure and cardiac death. Therefore, continued in-depth research on hypertrophic cardiac signaling is of high interest and essential for the development of new diagnostic and therapeutic approaches. Hypertrophy is the hearts response to pressure overload and involves extensive myocardial remodeling. Thickening of the left ventricular walls can compensate an increased pressure load temporarily, but over time pressure overload leads to dilation and stiffening of the left ventricle resulting in heart failure. On molecular level pathological hypertrophic signaling in cardiomyocytes includes upregulation of fetal and fibrosis-associated gene expression and calcineurin/NFAT signaling. It is known that LMCD1, a Z-disk associated protein, is upregulated in heart tissue of patients with hypertrophic and dilated cardiomyopathy, as well as various in vitro and in vivo models of maladaptive cardiac hypertrophy. We and others have shown that Lmcd1 overexpression induces pathological cardiac hypertrophy in vitro and in vivo. Furthermore, we have shown that Lmcd1 downregulation diminishes hypertrophic signaling in biomechanically stretched isolated cardiomyocytes. In line with this, we have found that in a model of advanced pathological myocardial hypertrophy, induced by severe pressure-overload due to transverse aortic banding (TAC), Lmcd1-deficiency blunts hypertrophic signaling and even reduces maladaptive morphological and functional alterations. In current experiments we are studying the effects of Lmcd1 downregulation on neurohumoral-induced cardiac hypertrophy in vitro and in vivo. In vitro we analyze the effects of Lmcd1 downregulation on isolated neonatal rat ventricular cardiomyocytes (NRVCM) with pro-hypertrophic stimulation using phenylephrine (PE) or angiotensin-II (AngII). For in vivo studies we use a model of mild pressure overload and hypertension due to low dose AngII infusion, to analyze early stages of maladaptive hypertrophy. Our most recent results show that Lmcd1 downregulation in NRVCM significantly reduces PE- and AngII-induced activation of hypertrophic signaling, including the expression of the fetal genes NppA and NppB and the calcineurin-responsive transcript Rcan1-4. In line with this, we found that in mice AngII-induced upregulation of fetal (NppA, Rcan1-4, Myh7, Acta1) as well as fibrosis-associated genes (Col1a1, Col3a1, Tgf-β, Postn) was significantly reduced in Lmcd1-deficient (KO) compared to control (WT) mice. In addition, we found that Lmcd1-deficiency significantly counteracts AngII-induced thickening of the left ventricular anterior and posterior walls (LVAW and LVPW), thereby impeding the decrease in left ventricular inner diameter (LVID) (WT-NaCl n=12, KO-NaCl n=11, WT-AngII n=11, KO-AngII n=9: ±SEM [mm]: LVAW: WT-NaCl 0.63±0.03, WT-AngII 0.75±0.03 vs KO-AngII 0.58±0.04, p<0.01; LVPW: WT-NaCl 0.75±0.04, WT-AngII 0.88±0.04 vs KO-AngII 0.69±0.04, p<0.01; LVID: WT-NaCl 4.16±0.1; WT-AngII 3.82±0.11 vs KO-AngII 4.30±0.13, p<0.01). Taken together, our data demonstrate that Lmcd1 is an important modulator of hypertrophic responses in the heart and not only affects late stages with heart failure, but even attenuates early stages of maladaptive hypertrophic alterations.

https://dgk.org/kongress_programme/jt2023/aP571.html