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Proteo-transcriptional architecture of human pressure overload: implications for heart failure

ABSTRACT: Chronic pressure overload initiates a series of molecular alterations in the human heart that predate macroscopic organ-level remodeling and downstream heart failure (HF). We hypothesized that integrating easily accessible circulating mediators (proteome) with their expression in the heart (transcriptome) may prioritize targets for study in human pressure overload. Among individuals with severe aortic stenosis (AS)—a pressure overload state—we measured the circulating proteome (Olink) and examined associations with myocardial structure/function (N=519), cardiac MRI-based tissue fibrosis (N=145), and outcomes in AS (N=802). We constructed proteomic signatures of cardiac remodeling and tested their association with HF in the UK Biobank (N=36,668). For proteo-transcriptional integration, we examined a "remodeling proteome” prioritized by proteome-phenotype relations at the transcriptional level via single nuclear RNA-sequencing (snRNA-seq) in 20 human hearts (11 with AS at the time of surgical aortic valve replacement [AVR] and 9 donor hearts not used for transplantation). We identified three principal components of myocardial remodeling (across 12 echocardiographic measures in 503 patients with AS) loaded on cardiac morphology, systolic, and diastolic function traits. Proteins associated with these components (the “remodeling proteome”) specified both known and novel mediators of fibrosis, hypertrophy, and oxidative stress, several of which were associated with interstitial fibrosis by cardiac MRI. Proteomic signatures of remodeling were strongly linked to mortality (AS cohort and UK Biobank) and incident HF (UK Biobank). At a myocardial level, we observed broad differential expression of genes encoding the remodeling proteome between AS and donor hearts, featuring convergent fibrosis pathways (WNT9A, ITGA6, AGRN, CRIM1, SEMA4C, LAYN, PTX3, HMOX1) and metabolic-inflammatory signaling (ENPP2/ATX, TNF), among others. Differential expression of proteo-transcriptionally prioritized genes was prominent in fibroblasts, cardiomyocytes, and endothelial cells. Proteo-transcriptional prioritization in human pressure overload hearts identifies both known and novel targets that are mechanistically relevant to HF pathogenesis. Future integrative studies to index circulating biomarkers over time to myocardial tissue level is warranted to inform pathways of HF progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262690 | GEO | 2025/05/01

REPOSITORIES: GEO

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Project description:Backgound: Cardiac pressure overload, for example in patients with aortic stenosis, induces irreversible damage in the myocardium leading to cardiac dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis. We therefore hypothesized that insufficient cardiac regeneration might contribute to the progression of pressure overload dependent disease. Here, we aimed to elucidate whether pressure overload in the regenerative stage shortly after birth could lead to a more adaptive cardiac response than in the non-regenerative stage in mice.nTAC in the non-regenerative stage induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, during induction of nTAC in the regenerative stage, cardiac function remained intact and this was associated with enhanced myocardial angiogenesis and innervation as well as increased cardiomyocyte proliferation, but neither hypertrophy nor fibrosis. Mechanistically, inhibition of cardiomyocyte proliferation and angiogenesis in nTAC in the regenerative phase by rapamycin triggered mortality and myocardial fibrosis, which both also similarly occurred upon inhibition of angiogenesis by PTK787, suggesting that both processes are essential for the adaptive cardiac response to nTAC. A comparative genome-wide transcriptomic analysis between hearts after nTAC in the regenerative versus the non-regenerative stage defined differentially expressed functional gene classes, and a related bioinformatics analysis suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response.tablished a new model of neonatal pressure-overload in mice, which when applied in the regenerative postnatal stage, triggers a purely adaptive myocardial response. Employing this model to identify new regulators might lead to novel therapeutic strategies to combat pressure overload induced myocardial disease.

Project description:Full Title: Transition from Compensated Hypertrophy to Systolic Heart Failure in the Spontaneously Hypertensive Rat: Structure, Function, and Transcript Analysis Gene expression changes and left ventricular remodeling associated with the transition to systolic heart failure (HF) were determined in the spontaneously hypertensive rat (SHR). By combining transcriptomics of left ventricles from six SHR with HF with changes in function and structure we aimed to better understand the molecular events underlying the onset of systolic HF compared to six age-matched, SHR with compensated hypertrophy. Left ventricle (LV) ejection fraction was depressed (82Â±4 to 52Â±3 %) in compensated vs. failing animals.Â Systolic blood pressure decreased and LV end-diastolic and systolic volume increased with HF.Â Failing SHR hearts also demonstrated increases in left and right ventricular mass relative to non-failing SHRs.Â Â LV papillary muscle force development and shortening velocity decreased, Î²-adrenergic responsiveness was depressed, myocardial stiffness and myocardial fibrosis increased with HF relative to non-failing animals. Initial micro-array analysis revealed that 1,431 transcripts were differentially expressed with HF compared to non-failing SHR (p<0.05). Of the identified transcripts, lipopolysaccharide binding protein, the most highly expressed transcript with HF, was negatively correlated to myocardial force while elevated expression of the collagen cross-linking enzyme lysyl oxidase correlated positively with muscle stiffness. Besides these individual transcripts, gene set enrichment analysis (GSEA) identified multiple enriched pathways with HF, most prominent of the altered signaling pathways involved TGF-Î² and insulin signaling. GESA analysis additionally identified altered gene sets involving inflammation, oxidative stress, cell degradation and cell death, among others (all p<0.01). In contrast to diastolic HF where few transcripts are reported to be altered, our data indicate multiple genes and pathways involved in a variety of biological processes characterize the onset of systolic HF, consistent with many functional and structural changes present in the failing hypertensive heart. Comprehensive gene expression profiling of heart failure Rat model vs control.

Project description:Full Title: Transition from Compensated Hypertrophy to Systolic Heart Failure in the Spontaneously Hypertensive Rat: Structure, Function, and Transcript Analysis Gene expression changes and left ventricular remodeling associated with the transition to systolic heart failure (HF) were determined in the spontaneously hypertensive rat (SHR). By combining transcriptomics of left ventricles from six SHR with HF with changes in function and structure we aimed to better understand the molecular events underlying the onset of systolic HF compared to six age-matched, SHR with compensated hypertrophy. Left ventricle (LV) ejection fraction was depressed (82±4 to 52±3 %) in compensated vs. failing animals. Systolic blood pressure decreased and LV end-diastolic and systolic volume increased with HF. Failing SHR hearts also demonstrated increases in left and right ventricular mass relative to non-failing SHRs. LV papillary muscle force development and shortening velocity decreased, β-adrenergic responsiveness was depressed, myocardial stiffness and myocardial fibrosis increased with HF relative to non-failing animals. Initial micro-array analysis revealed that 1,431 transcripts were differentially expressed with HF compared to non-failing SHR (p<0.05). Of the identified transcripts, lipopolysaccharide binding protein, the most highly expressed transcript with HF, was negatively correlated to myocardial force while elevated expression of the collagen cross-linking enzyme lysyl oxidase correlated positively with muscle stiffness. Besides these individual transcripts, gene set enrichment analysis (GSEA) identified multiple enriched pathways with HF, most prominent of the altered signaling pathways involved TGF-β and insulin signaling. GESA analysis additionally identified altered gene sets involving inflammation, oxidative stress, cell degradation and cell death, among others (all p<0.01). In contrast to diastolic HF where few transcripts are reported to be altered, our data indicate multiple genes and pathways involved in a variety of biological processes characterize the onset of systolic HF, consistent with many functional and structural changes present in the failing hypertensive heart.

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Proteo-transcriptional architecture of human pressure overload: implications for heart failure

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