Cardiac transcriptional and metabolic changes following thoracotomy

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

Fibin regulates cardiomyocyte hypertrophy and causes protein-aggregate-associated cardiomyopathy in vivo

Despite the identification of numerous molecular pathways modulating cardiac hypertrophy its pathogenesis is not completely understood. In this study we define an unexpected role for Fibin (“fin bud initiation factor homolog”) in cardiomyocyte hypertrophy. Via gene expression profiling in hypertrophic murine hearts after transverse aortic constriction we found a significant induction of Fibin. Moreover, Fibin was upregulated in another mouse model of cardiac hypertrophy (calcineurin-transgenics) as well as in patients with dilated cardiomyopathy. Immunoflourescence microscopy revealed subcellular localization of Fibin at the sarcomeric z-disc. Overexpression of Fibin in neonatal rat ventricular cardiomyocytes revealed a strong anti-hypertrophic effect through inhibiting both, NFAT- and SRF-dependent signalling. In contrast, transgenic mice with cardiac-restricted overexpression of Fibin developed dilated cardiomyopathy, accompanied by induction of hypertrophy-associated genes. Moreover, Fibin overexpression accelerated the progression to heart failure in the presence of prohypertrophic stimuli such as pressure overload and calcineurin overexpression. Histological and ultrastructural analyses surprisingly showed large protein aggregates containing Fibin. On the molecular level, aggregate formation was accompanied by an induction of the unfolded protein response subsequent UPR-mediated apoptosis and autophagy. Taken together, we identified Fibin as a novel potent negative regulator of cardiomyocyte hypertrophy in vitro. Yet, heart-specific Fibin overexpression in vivo causes development of a protein-aggregate-associated cardiomyopathy. Because of close similarities to myofibrillar myopathies, Fibin represents a candidate gene for cardiomyopathy and Fibin transgenic mice may provide additional mechanistic insight into aggregate formation in these diseases

Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations

Growing evidence suggests an altered gut microbiome in patients with heart failure (HF). However, the exact interrelationship between microbiota, HF, and its consequences on the metabolome are still unknown. We thus aimed here to decipher the association between the severity and progression of HF and the gut microbiome composition and circulating metabolites. Using a mouse model of transverse aortic constriction (TAC), gut bacterial diversity was found to be significantly lower in mice as early as day 7 post-TAC compared to Sham controls (p = 0.03), with a gradual progressive decrease in alpha-diversity on days 7, 14, and 42 (p = 0.014, p = 0.0016, p = 0.0021) compared to day 0, which coincided with compensated hypertrophy, maladaptive hypertrophy, and overtly failing hearts, respectively. Strikingly, segregated analysis based on the severity of the cardiac dysfunction (EF < 40% vs. EF 40–55%) manifested marked differences in the abundance and the grouping of several taxa. Multivariate analysis of plasma metabolites and bacterial diversity produced a strong correlation of metabolic alterations, such as reduced short-chain fatty acids and an increase in primary bile acids, with a differential abundance of distinct bacteria in HF. In conclusion, we showed that HF begets HF, likely via a vicious cycle of an altered microbiome and metabolic products

AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure

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

The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice

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-gamma 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

FYCO1 Regulates Cardiomyocyte Autophagy and Prevents Heart Failure Due to Pressure Overload In Vivo

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, Fyco/-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. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation