KLF15-Wnt–Dependent Cardiac Reprogramming Up-Regulates SHISA3 in the Mammalian Heart

Noack, Claudia; Iyer, Lavanya M; Liaw, Norman Y.; Schoger, Eric; Khadjeh, Sara; Wagner, Eva; Woelfer, M.; Zafiriou, Maria-Patapia; Milting, Hendrik; Sossalla, Samuel; Streckfuss-Boemeke, K; Hasenfuß, Gerd; Zimmermann, Wolfram‐Hubertus; Zelarayán, Laura C.

doi:10.1016/j.jacc.2019.07.076

Cited by 22 publications

(14 citation statements)

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“…This was accompanied by endothelial cells with an active angiogenic profile and supports previous studies showing a vascular program induced by cardiomyocytes with Wnt activation in the adult heart 41 . Other studies showed that HIF1α in cardiomyocytes was inversely correlated with capillarization 7 , indicating that cardiomyocytes are central for the phenotypic change of surrounding cells. We observed that stress scores were significantly increased in TAC cardiomyocytes at CH while these scores were less significant at FH, indicating a transcriptional adaptation in advanced remodeling.…”

Section: Discussionmentioning

confidence: 92%

“…However, activation of Wnt/β-catenin signaling specifically in cardiomyocytes resulted in molecular and phenotypic features of pathological remodeling 3 . This was characterized by a cell-autonomous effect triggered by TCF7L2/β-catenin transcriptional activation in cardiomyocytes, resulting in cell-dedifferentiation with increased cell cycle activity and heart failure 3 , 6 , 7 . These data suggested a primary regenerative function of Wnt activation, which is suppressed due to the lack of tissue plasticity in the adult heart.…”

Section: Introductionmentioning

confidence: 99%

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Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling

et al. 2023

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Aberrant Wnt activation has been reported in failing cardiomyocytes. Here we present single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific Wnt activation (β-catΔex3) as well as with compensatory and failing hypertrophic remodeling. We show that functional enrichment analysis points to an involvement of extracellular vesicles (EVs) related processes in hearts of β-catΔex3 mice. A proteomic analysis of in vivo cardiac derived EVs from β-catΔex3 hearts has identified differentially enriched proteins involving 20 S proteasome constitutes, protein quality control (PQC), chaperones and associated cardiac proteins including α-Crystallin B (CRYAB) and sarcomeric components. The hypertrophic model confirms that cardiomyocytes reacted with an acute early transcriptional upregulation of exosome biogenesis processes and chaperones transcripts including CRYAB, which is ameliorated in advanced remodeling. Finally, human induced pluripotent stem cells (iPSC)-derived cardiomyocytes subjected to pharmacological Wnt activation recapitulated the increased expression of exosomal markers, CRYAB accumulation and increased PQC signaling. These findings reveal that secretion of EVs with a proteostasis signature contributes to early patho-physiological adaptation of cardiomyocytes, which may serve as a read-out of disease progression and can be used for monitoring cellular remodeling in vivo with a possible diagnostic and prognostic role in the future.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling

et al. 2023

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“…PS-3 is a scaffold protein mediating the Wnt/beta-catenin signaling pathway (20). Recent data identify PS-3 involvement in pathological adverse vascular remodeling (21), suggesting a detrimental role of PS-3 in CAD development. A large number of studies have identified PAF-AH (also known as lipoproteinassociated phospholipase A2, Lp-PLA 2 ) as a biomarker of vascular inflammation and atherosclerosis (22).…”

Section: Discussionmentioning

confidence: 99%

Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans

Ferrannini

Manca

Ferrannini

et al. 2022

Front. Cardiovasc. Med.

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BackgroundProteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms.AimWe aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits.Materials and MethodsThe CAPIRE study (ClinicalTrials.gov Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45–75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD+) or completely clean arteries (CAD−) and either ≤ 1 risk factor (RF+) or ≥3 risk factors (RF−) (based on history, blood pressure, glycemia, lipids, and smoking).ResultsOf 544 individuals, 39% were atypical (93 CAD+/RF−; 120 CAD−/RF+) and 61% typical (102 CAD+/RF+; 229 CAD−/RF−). In the comparison with CAD+/RF− adjusted for sex and age, CAD−/RF+ was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUCROC's of 0.72–0.81 (overall p = 1.0e−38). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA1c, and smoking.ConclusionsIn a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA1c. These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets.

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“…and Cebpb) were downregulated by β-catenin in adult cardiomyocytes and are associated with the switch from glycolytic to oxidative phosphorylation (Bhalla et al, 2014;Pearen et al, 2008;Pearen et al, 2006). Of note, Klf15 has been identified as a key regulator of cardiomyocyte fatty acid metabolism (Prosdocimo et al, 2014), and has exhibits mutually antagonistic signalling with β-catenin in cardiac development (Noack et al, 2019;Noack et al, 2012). Interestingly, induction of cardiomyocyte glycolytic metabolism was associated with loss of Klf15 signalling (Shao et al, 2018).…”

Section: 5mentioning

confidence: 99%

Transcriptional regulation of mammalian heart regeneration

Quaife-Ryan¹

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There are 26 million patients living with heart failure (HF), which is one of the primary causes of death worldwide. HF is a pathological process characterised by heart muscle damage leading to progressive deterioration of the heart's pumping and/or filling capabilities. This process decreases cardiac output and results in an inability to meet metabolic demand and ultimately sudden cardiac death. The most common cause of HF is coronary artery disease like myocardial infarction (MI). The adult heart is the least regenerative organ in the body, hence heart muscle is never replaced after injury, making HF a chronic and incurable disease. The inability of the adult mammalian heart to regenerate represents a major limitation in cardiovascular medicine and HF management. Currently all medical therapies for HF seek to salvage viable cardiac tissue, prevent maladaptive remodelling or improve the contractility of the failing heart but crucially, no cardioregenerative therapies exist. As such, a new class of regenerative therapeutics would revolutionise the treatment of HF patients, for which there have not been any approvals for new drug classes for 20 years.

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KLF15-Wnt–Dependent Cardiac Reprogramming Up-Regulates SHISA3 in the Mammalian Heart

Cited by 22 publications

References 42 publications

Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling

Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling

Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans

Transcriptional regulation of mammalian heart regeneration

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