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Visual Abstract, Highlights • FYCO1, a component of the autophagic machinery, is highly expressed in the heart and a potent inducer of cardiomyocyte autophagy. • Loss of FYCO1 in vivo inhibits adaptation to starvation or biomechanical stress of the heart by an abrogated increase of autophagic flux and results in contractile dysfunction. • Heart specific overexpression of FYCO1 improves autophagic flux and rescues contractile dysfunction following pressure overload., Summary Autophagy is a cellular degradation process that has been implicated in diverse disease processes. The authors provide evidence that FYCO1, a component of the autophagic machinery, is essential for adaptation to cardiac stress. Although the absence of FYCO1 does not affect basal autophagy in isolated cardiomyocytes, it abolishes induction of autophagy after glucose deprivation. Likewise, Fyco1-deficient mice subjected to starvation or pressure overload are unable to respond with induction of autophagy and develop impaired cardiac function. FYCO1 overexpression leads to induction of autophagy in isolated cardiomyocytes and transgenic mouse hearts, thereby rescuing cardiac dysfunction in response to biomechanical stress.

Pathological remodeling of the extracellular matrix is a hallmark of cardiovascular disease, causing cardiac dysfunction by reducing ejection fraction and impaired electrical conductance, leading to arrythmias. Hence, accurate quantification of fibrosis deposition in histological sections is of extreme importance for preclinical and clinical studies. Current automatic tools do not perform well under variant conditions. Moreover, users do not have the option to evaluate data from staining methods of their choice according to their purpose. To overcome these challenges, we underline a novel machine learning-based tool (FibroSoft) and we show its feasibility in a model of cardiac hypertrophy and heart failure in mice. Our results demonstrate that FibroSoft can identify fibrosis in diseased myocardium and the obtained results are user-independent. In addition, the results acquired using our software strongly correlate to those obtained by Western blot analysis of collagen 1 expression. Additionally, we could show that this method can be used for Masson’s Trichrome and Picosirius Red stained histological images. The evaluation of our method also indicates that it can be used for any particular histology segmentation and quantification. In conclusion, our approach provides a powerful example of the feasibility of machine learning strategies to enable automatic analysis of histological images.

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach. Supplementary Information The online version contains supplementary material available at 10.1007/s00395-021-00880-w.

Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also largely abolished macrophage infiltration and fibrosis induced by pressure overload. Taken together, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which links anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1. In a broader perspective, these findings support the notion that cardiomyocyte growth and inflammation are more intertwined than previously anticipated., Rangrez et al. show that overexpression of the HECT domain E3 ubiquitin protein ligase 3 (HectD3) reduces cardiac hypertrophy while reducing macrophage infiltration in mice. This study provides a cardioprotective mechanism, where HectD3 targets SUMO2 and Stat1 to exert its anti-hypertrophic and anti-inflammatory effects.

We and others have shown that LMCD1 expression levels are upregulated in various in vitro and in vivo models of hypertrophy and that LMCD1 is necessary and sufficient to induce cardiomyocyte hypertrophy in vitro . We successfully generated a new mouse line with a conditional cardiac knockout of LMCD1. We performed echocardiographic, morphometric, and molecular analysis in these LMCD1-deficient and appropriate control-mice under basic conditions as well as 14 days after transverse aortic banding (TAC)-induced left ventricular (LV) pressure overload. Our aim was to investigate the hypothesis of potential beneficial effects of LMCD1-downregulation in vivo . These knockout (KO)-mice revealed under basic conditions a significant reduction of LMCD1 in the heart to

Non-cardiac surgery is associated with significant cardiovascular complications. Reported mortality rate ranges from 1.9% to 4% in unselected patients. A postoperative surge in pro-inflammatory cytokines is a well-known feature and putative contributor to these complications. Despite much clinical research, little is known about the biomolecular changes in cardiac tissue following non-cardiac surgery. In order to increase our understanding, we analyzed whole-transcriptional and metabolic profiling data sets from hearts of mice harvested two, four, and six weeks following isolated thoracotomy. Hearts from healthy litter-mates served as controls. Functional network enrichment analyses showed a distinct impact on cardiac transcription two weeks after surgery characterized by a downregulation of mitochondrial pathways in the absence of significant metabolic alterations. Transcriptional changes were not detectable four and six weeks following surgery. Our study shows distinct and reversible transcriptional changes within the first two weeks following isolated thoracotomy. This coincides with a time period, in which most cardiovascular events happen.

Objective: In this study, using a Yeast two-hybrid screen, we identified the HECT domain-containing E3 ubiquitin ligase 3 (HECTD3) as one of the novel cardiac binding partners of SUMO2. Present study thus focusses on deciphering the cardiac function of HECTD3. Methods and Results: HECTD3-SUMO2 interaction was further validated by co-immunoprecipitation analysis. Interesting, adenovirus-mediated overexpression of HECTD3 in neonatal rat ventricular cardiomyocytes (NRVCMs) resulted in downregulation of endogenous as well as overexpressed SUMO2. Proteasome inhibitor MG132 treatment however inhibited HECTD3-mediated SUMO2 downregulation, suggesting SUMO2 as a likely substrate of HECTD3 in ubiquitin-proteasome system dependent protein degradation. To get further insights into cardiac substrates of HECTD3, we performed mass-spectrometry analysis of NRVCM protein lysate. Interestingly, several proteins from interferon signaling, including signal transducer and activator of transcription-1 (STAT1), were significantly downregulated by HECTD3 overexpression. Functional dissection of HECTD3-SUMO2-STAT1 interaction revealed attenuation of cellular hypertrophy and LPS mediated activation of inflammatory cascade in NRVCMs. Importantly, in vitro findings were consistent in vivo , where, AAV-9 mediated overexpression of HECTD3 substantially reduced cardiac hypertrophy and fibrosis, inhibited activation of STAT1-mediated downstream signaling, and attenuated infiltration of inflammatory cells to the heart after transverse-aortic constriction or Angiotensin II treatment. Conclusions: In conclusion, we describe here a novel cardioprotective mechanism involving the ubiquitin ligase HECTD3, which exerts anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and its sumoylation target STAT1. This “dual pathway” inhibition may be exploited for the prevention and/or therapy of cardiac hypertrophy and heart failure.