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Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis

ABSTRACT: Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE168742 | GEO | 2022/03/03

REPOSITORIES: GEO

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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

Project description:Background: Pathological cardiac overload triggers maladaptive myocardial remodeling that predisposes to the development of heart failure. The contribution of long non-coding RNAs (lncRNAs) to intercellular signaling during cardiac remodeling is largely unknown. Methods: We analyzed the expression of Gadlor 1 and Gadlor2 lncRNAs in mouse hearts, mouse cardiac cells, extracellular vesicles (EVs), human failing hearts as well as patient serum. Gadlor knock-out (KO) mice were generated and analyzed. The effect of Gadlor knock-out and Gadlor overexpression during cardiac pressure overload induced by transverse aortic constriction (TAC) was analyzed by echocardiography, histological analyses and RNA sequencing in isolated cardiac cells. Gadlor1/2 interaction partners were identified by RNA antisense purification coupled with mass-spectrometry (RAP-MS). Results: In the heart, the related lncRNAs Gadlor1 and 2 are mainly expressed in endothelial cells and to a lesser extent in fibroblasts. Gadlor1/2 are upregulated in failing mouse hearts as well as in the myocardium and in serum of heart failure patients. Interestingly, Gadlor1 and 2 are secreted from endothelial cells within EVs, which are taken up by cardiomyocytes. Gadlor-KO mice exerted reduced cardiomyocyte hypertrophy, diminished myocardial fibrosis and improved cardiac function, but paradoxically suffered from sudden death during prolonged overload. Gadlor overexpression, in turn, triggered hypertrophy, fibrosis and cardiac dysfunction. Mechanistically, Gadlor1 and Gadlor2 inhibit angiogenic gene expression in endothelial cells, while promoting the expression of pro-fibrotic genes in cardiac fibroblasts. In cardiomyocytes, Gadlor1/2 upregulate mitochondrial genes, but downregulate angiogenesis genes, while interacting with the transcriptional regulator Glyr1 and the calcium/calmodulin-dependent protein kinase type II (CaMKII), entailing cardiomyocyte hypertrophy and perturbed cardiomyocyte calcium dynamics. Conclusions: We describe that Gadlor1 and 2, two related, novel lncRNAs, are upregulated in cardiac pathological overload and are secreted from endothelial cells within EVs. Gadlor1/2 induce cardiac dysfunction, cardiomyocyte hypertrophy and myocardial fibrosis by exerting heterocellular effects on cardiac cellular gene-expression and by affecting calcium dynamics in cardiomyocytes, which take up the Gadlor1/2 by EV mediated transfer from endothelial cells. Targeted inhibition of Gadlor lncRNAs in endothelial cells or fibroblasts might serve as therapeutic strategy in the future.

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Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis

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