Biology subjects

Beauloye, C.

Publications and source records attributed to Beauloye, C..

5 recordsLinked to original sources

bioRxiv2026

Platelet GARP-dependent activation of TGF-β1 limits inflammation and promotes cardiac repair after myocardial infarction

Platelets are increasingly recognized as active regulators of inflammation beyond their canonical hemostatic functions. Although platelets rapidly accumulate in the injured myocardium after myocardial infarction (MI), the mechanisms by which they coordinate the inflammatory response remain poorly understood. Glycoprotein A repetitions predominant (GARP) is a membrane receptor that presents latent transforming growth factor-{beta}1 (TGF-{beta}1) on activated platelets and supports its activation. Given the central role of TGF-{beta}1 in inflammation and tissue repair, we hypothesized that platelet GARP-dependent activation of TGF-{beta}1 regulates inflammatory resolution and repair after MI. Using mice with megakaryocyte-and platelet-specific Garp deletion, we demonstrate that loss of platelet GARP selectively impaired generation of bioactive TGF-{beta}1 without altering platelet reactivity. Following permanent coronary artery ligation, platelet-specific Garp deficiency markedly increased mortality from ventricular rupture and exacerbated adverse left ventricular remodeling, independent of initial infarct size. Transcriptomic and histological analyses revealed heightened endothelial cell activation, increased leukocyte recruitment, delayed inflammatory resolution, and defective extracellular matrix deposition in the absence of platelet GARP. Mechanistically, platelet GARP-dependent TGF-{beta}1 signaling restrained endothelial activation after MI. Together, these findings identify platelet GARP-mediated activation of TGF-{beta}1 as a critical platelet-intrinsic counter-regulatory checkpoint that limits endothelial-driven inflammation and promotes infarct stabilization. Our study reveals an unexpected protective immunoregulatory function of platelets in cardiac repair after ischemic injury.

pathology↗

bioRxiv2025

skNAC is a Key Driver of Cardiomyocyte Integrity Against Pathological Cardiac Hypertrophy and Heart Failure

Chronic pressure overload induces cardiac hypertrophy and heart failure through coordinated alterations in proteome homeostasis, metabolism and sarcomere organisation. The muscle-specific -isoform of the nascent polypeptide-associated complex (skNAC) is essential for sarcomere assembly during development, but its role in adult hearts remains largely unknown. Here, we show that skNAC expression is reduced in hypertrophic cardiomyocytes, mouse models of pressure overload, and human hypertrophic hearts, in association with disease severity. Cardiomyocyte-specific skNAC deletion results in basal hypertrophy, systolic dysfunction, and premature death, and exacerbates pressure overload-induced heart failure. At the molecular level, skNAC associates with ribosomes and is required for sarcomere organisation maintenance, while its loss induces autophagy and ultrastructural defects. Integrated transcriptomic and proteomic analyses reveal early downregulation of metabolic gene expression despite increased abundance of corresponding proteins, indicating compensatory metabolic responses. Gain-of-function studies confirm a protective role against hypertrophy. Together, these data establish skNAC as a key regulator of cardiac proteome homeostasis and metabolic adaptation during pathological remodelling.

physiology↗

bioRxiv2024

When the liver is in poor condition, so is the heart - cardiac remodelling in MASH mouse models

Metabolic dysfunction-associated steatohepatitis (MASH) confers a risk for cardiovascular diseases in patients. Animal models may help exploring the mechanisms linking liver and heart diseases. Hence, we explored the cardiac phenotype in MASH mouse models. MethodsWe evaluated pathological alterations in liver and heart in foz/foz mice fed a high fat diet for 24 or 60 weeks and in C57BL/6J mice fed a high fat, high fructose diet for 60 weeks. Angiotensin ll (Angll) was used as an additional cardiovascular stressor. ResultsFoz/foz mice with fibrosing MASH developed cardiac hypertrophy with adverse cardiac remodelling not seen in WT similarly fed the high fat diet. Angll caused hypertension and upregulated the expression of genes contributing to pathological cardiac hypertrophy (Nppa, Myh7) more severely so in foz/foz mice than in controls. After 60 weeks of HFD, while liver disease had progressed to burn-out non steatotic MASH with hepatocellular carcinoma in 50% of the animals, the cardiomyopathy did not. In an independent model (C57BL/6J mice fed a high fat, high fructose diet), moderate fibrosing MASH is associated with cardiac fibrosis and dysregulation of genes involved in pathological remodelling (Collal, Col3al, Vim, Myh6, Slc2al). ConclusionAnimals with MASH present consistent adverse structural changes in the heart with no patent alteration of cardiac function even when stressed with exogenous Angll. Liver disease, and not overfeeding or aging alone, is associated with this cardiac phenotype. Our findings confirm foz/foz mice as suitable for studying links between MASH and heart structural changes ahead of heart failure.

physiology↗

bioRxiv2023

Sodium myo-inositol cotransporter-1, SMIT1, promotes cardiac hypertrophy and fibrosis in pressure overloaded mouse hearts

AimsRecent clinical studies have reported that myo-inositol is consistently elevated in plasma of patients with heart failure (HF), yet its role in cardiac dysfunction remains poorly understood. Myo-inositol is specifically transported into cells by the sodium-myo-inositol co-transporter-1 (SMIT1), a member of the sodium-glucose co-transporter (SGLT) family expressed in the heart. While myo-inositol is essential for phosphoinositide signaling, osmoregulation, and metabolic homeostasis, dysregulation of SMIT1-mediated myo-inositol transport may contribute to key pathological mechanisms in HF. This study aims to elucidate the role of SMIT1 in the failing heart, especially during left ventricular remodeling that precedes it. Methods and resultsWe used a mouse model of pressure overload induced by transverse aortic constriction in wild-type (WT) mice and mice lacking SMIT1 (Smit1-/-), and primary cultured cardiomyocytes. By combining molecular, structural and functional studies, RNA-sequencing, and calcium measurements, we demonstrate the contribution of myo-inositol and SMIT1 to pathological hypertrophy and the progression towards HF. We found that in comparison to WT controls, Smit1-/- mice were protected against aortic banding induced systolic dysfunction, cardiac fibrosis and hypertrophy. This hypertrophic response was driven by SMIT1 expression in cardiomyocytes, where it favors intracellular myo-inositol and Na+ entry, leading to inositol 1,4,5-trisphosphate (IP3)- and Ca2+-dependent pro-hypertrophic signaling. Following hemodynamic stress, deletion of SMIT1 significantly altered IP3/calcium effectors, including Carabin, which modulates cardiac hypertrophy through inhibition of the calcineurin/NFAT and Ras/ERK1/2 pathways. ConclusionsThis work provides important insights into the role of myo-inositol and SMIT1 in cardiomyocytes. We demonstrate that SMIT1 is a key driver of pathological hypertrophy by inducing an IP3/Ca2+-dependent pro-hypertrophic transcriptional reprogramming in cardiomyocytes. These findings identify SMIT1 as a promising therapeutic target for preventing or treating pathological cardiac hypertrophy and HF.

cell biology↗

bioRxiv2020

Beta-3 Adrenoreceptors protect from hypertrophic remodelling through AMP-Activated Protein Kinase and Autophagy.

AimsThe abundance of beta3-adrenergic receptors ({beta}3-ARs) is upregulated in diseased human myocardium. We previously showed that cardiac-specific expression of {beta}3-AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analyzed signalling pathways involved in the anti-hypertrophic effect of {beta}3-AR. MethodsIn vitro hypertrophic responses to phenylephrine (PE) were analyzed in neonatal rat ventricular myocytes (NRVM) infected with a recombinant adenovirus expressing the human {beta}3-AR (AdVh{beta}3). We confirmed results in mice with cardiomyocyte-specific moderate expression of human {beta}3-AR ({beta}3-TG) and WT littermates submitted to thoracic transverse aortic constriction (TAC) for 9 weeks. ResultsWe observed a colocalization of {beta}3-AR with the AMP-activated protein kinase (AMPK) both in neonatal rat andin adult mouse cardiomyocytes. Treatment of NRVM with PE induced hypertrophy and a decrease in phosphorylation of Thr172-AMPK (/2, p=0.0487) and phosphorylation of Ser79- acetyl-CoA carboxylase (ACC) (/2.6, p=0.0317), inducing an increase in phosphorylated Ser235/236 S6 protein (x2.5, p=0.0367) known to be involved in protein synthesis. These effects were reproduced by TAC in WT mice, but restored to basal levels in {beta}3-AR expressing cells/mice. siRNA targeting of AMPK partly abrogated the anti-hypertrophic effect of {beta}3-AR in response to PE in NRVM (x1.3, p<0.0001). Concomitant with hypertrophy, autophagy measured by microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio and p62 abundance was decreased by PE in NRVM (/2.6, p=0.0010 and x3, p=0.0016, respectively) or TAC in WT mice (/5.4, p=0.0159); and preserved in human {beta}3-AR expressing cells and mice, together with reduced hypertrophy. ConclusionsCardiac-specific moderate expression of {beta}3-AR inhibits the hypertrophic response in part through AMPK activation followed byinhibition of protein synthesis and preservation of autophagy. Activation of the cardiac {beta}3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodelling.

cell biology↗