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Post-myocardial infarction heart failure dysregulates the bone vascular niche.

ABSTRACT: The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1β production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease.

SUBMITTER: Hoffmann J

PROVIDER: S-EPMC8233308 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Post-myocardial infarction heart failure dysregulates the bone vascular niche.

Hoffmann Jedrzej J Luxán Guillermo G Abplanalp Wesley Tyler WT Glaser Simone-Franziska SF Rasper Tina T Fischer Ariane A Muhly-Reinholz Marion M Potente Michael M Assmus Birgit B John David D Zeiher Andreas Michael AM Dimmeler Stefanie S

Nature communications 20210625 1

The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of infl ...[more]

PMID: 34172720

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Project description:AimsSarcolipin (SLN) is a key regulator of sarcoplasmic reticulum calcium-ATPase (SERCA)2a, which handles intracellular calcium re-uptake. This study was aimed to investigate the involvement of SLN in post-myocardial infarction (MI) heart failure (HF) in diabetes.Methods and resultsDiabetes/MI rat models were established. Altered SLN expression in diabetic hearts was screened out by microarray. A myocardiotropic viral vector was used to deliver siRNA to silence SLN. DNA methylation was evaluated by bisulfite sequencing. Cardiac functions were evaluated by invasive haemodynamic examinations. The SERCA2a activity, cytoplasmic calcium concentration ([Ca2+ ]i ), calcium spark, and myocyte contraction were detected. Correlation between HF and diabetes was analysed in a cohort consisted of 101 ST-segment elevated myocardial infarction (STEMI) patients between 2017 and 2019 [53.54 ± 4.64 years old; 61.4% male gender; HbA1c% 6.15 ± 2.00; and left ventricular ejection fraction (LVEF%) 40.64 ± 3.20%]. SLN expression was evaluated in left ventricular tissue sample from six STEMI patients complicated with diabetes and six STEMI patients without diabetes. Expressions of DNA methyltransferase 1a and DNA methyltransferase 3 were reduced in diabetic hearts, leading to down-regulation of SLN promoter methylation, resulting in increased SLN expression in rats. Impaired heart systolic functions were found in experimental diabetic MI rats, which were attenuated by SLN silencing. SERCA2a activity reduction and [Ca2+ ]i elevation were attenuated by SLN silencing in diabetic animal hearts and high-glucose incubated primary myocytes. SLN silencing suppressed calcium sparks and improved contraction and sarcoplasmic reticulum calcium re-uptake in high-glucose incubated primary myocytes. Expression of SLN was up-regulated in LV sampled from STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.05). LVEF% was reduced in STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.01). HbA1c% and LVEF% was related (r = -0.218, P = 0.028). Increased HbA1c% was correlated with reduced LVEF% after adjustment for age, sex, body mass index, cigarette smoking, creatinine, UA, low density lipoprotein, K+ , Na+ , and troponin I (adjusted odds ration = 0.75, 95% confidence interval 0.62-0.90, P = 0.002).ConclusionsDiabetes increases the vulnerability of STEMI patients to post-MI HF by down-regulating SLN promoter methylation, which further regulates SERCA2a activity via increasing cardiac SLN expression.

Project description:BackgroundHeart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery.MethodsWe used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF.ResultsIn the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4, and follistatin-related protein-3, as well.ConclusionsLarge-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.

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Post-myocardial infarction heart failure dysregulates the bone vascular niche.

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Post-myocardial infarction heart failure dysregulates the bone vascular niche.

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