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Tetranectin, a potential novel diagnostic biomarker of heart failure, is expressed within the myocardium and associates with cardiac fibrosis.

ABSTRACT: Heart failure (HF) screening strategies require biomarkers to predict disease manifestation to aid HF surveillance and management programmes. The aim of this study was to validate a previous proteomics discovery programme that identified Tetranectin as a potential HF biomarker candidate based on expression level changes in asymptomatic patients at future risk for HF development. The initial study consisted of 132 patients, comprising of HF (n?=?40), no-HF controls (n?=?60), and cardiac surgery patients (n?=?32). Serum samples were quantified for circulating levels of Tetranectin and a panel of circulating fibro-inflammatory markers. Cardiac tissue served as a resource to investigate the relationship between cardiac Tetranectin levels and fibrosis and inflammation within the myocardium. An independent cohort of 224 patients with or without HF was used to validate serum Tetranectin levels. Results show that circulating Tetranectin levels are significantly reduced in HF patients (p?

SUBMITTER: McDonald K

PROVIDER: S-EPMC7200823 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Tetranectin, a potential novel diagnostic biomarker of heart failure, is expressed within the myocardium and associates with cardiac fibrosis.

McDonald Kenneth K Glezeva Nadezhda N Collier Patrick P O'Reilly James J O'Connell Eoin E Tea Isaac I Russell-Hallinan Adam A Tonry Claire C Pennington Steve S Gallagher Joe J Ledwidge Mark M Baugh John J Watson Chris J CJ

Scientific reports 20200505 1

Heart failure (HF) screening strategies require biomarkers to predict disease manifestation to aid HF surveillance and management programmes. The aim of this study was to validate a previous proteomics discovery programme that identified Tetranectin as a potential HF biomarker candidate based on expression level changes in asymptomatic patients at future risk for HF development. The initial study consisted of 132 patients, comprising of HF (n = 40), no-HF controls (n = 60), and cardiac surgery p ...[more]

PMID: 32371911

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Project description:BACKGROUND:Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload-induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload-induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. METHODS:Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. RESULTS:Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow-depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction-induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with ?-smooth muscle actin or collagen 1? in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-?-induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO-FPCs compared with WT-FPCs. Polymerase chain reaction-based selective miRNA analysis revealed that transforming growth factor-?-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-?-induced fibrotic signaling in BM-FPCs. CONCLUSIONS:Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad-miRNA-21-mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

Project description:BACKGROUND:Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-?1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-?1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGF? family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGF? coreceptor that promotes TGF-?1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity. METHODS:We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction-induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. RESULTS:BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9-/- mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction-induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3. CONCLUSIONS:Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.

Project description:ImportanceTransverse tubule remodeling is a hallmark of heart failure. Cardiac bridging integrator 1 (cBIN1) is a circulating membrane scaffolding protein that is essential for transverse tubule health, and its plasma level declines with disease.ObjectiveTo determine if a cBIN1-derived score can serve as a diagnostic biomarker of heart failure with preserved ejection fraction (HFpEF).Design, setting, and participantsIn this cohort study, the cBIN1 score (CS) was determined from enzyme-linked immunoabsorbent assay-measured plasma cBIN1 concentrations from study participants in an ambulatory heart failure clinic at Cedars-Sinai Medical Center. Consecutive patients with a confirmed diagnosis of heart failure with preserved ejection fraction (HFpEF; defined by a left ventricular ejection fraction ≥50%) were recruited from July 2014 to November 2015 and compared with age-matched and sex-matched healthy volunteers with no known cardiovascular diagnoses and participants with risk factors for heart failure but no known HFpEF. Baseline characteristics and 1-year longitudinal clinical information were obtained through electronic medical records. Data analysis occurred from November 2016 to November 2017.Main outcomes and measuresThe analysis examined the ability of the CS and N-terminal pro-B-type natriuretic peptide (NT-proBNP) results to differentiate among patients with HFpEF, healthy control participants, and control participants with risk factors for heart failure. We further explored the association of the CS with future cardiovascular hospitalizations.ResultsA total of 52 consecutive patients with a confirmed diagnosis of HFpEF were enrolled (mean [SD] age, 57 [15] years; 33 [63%] male). The CS values are significantly higher in the patients with HFpEF (median [interquartile range (IQR)], 1.85 [1.51-2.28]) than in the 2 control cohorts (healthy control participants: median [IQR], -0.03 [-0.48 to 0.41]; control participants with risk factors only: median [IQR], -0.08 [-0.75 to 0.42]; P < .001). For patients with HFpEF, the CS outperforms NT-proBNP when the comparator group was either healthy control participants (CS: area under curve [AUC], 0.98 [95% CI, 0.96-1.00]; NT-proBNP level: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001) or those with risk factors (CS: AUC, 0.98 [95% CI, 0.97-1.00]; NT-proBNP: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001). Kaplan-Meier analysis of 1-year cardiovascular hospitalizations adjusted for age, sex, body mass index, and NT-proBNP levels reveals that patients with HFpEF with CS greater than or equal to 1.80 have a hazard ratio of 3.8 (95% CI, 1.3-11.2; P = .02) for hospitalizations compared with those with scores less than 1.80.Conclusions and relevanceIf further validated, the plasma CS, a marker of transverse tubule dysfunction, may serve as a biomarker of cardiomyocyte remodeling that has the potential to aide in the diagnosis of HFpEF.

Dataset Information

Tetranectin, a potential novel diagnostic biomarker of heart failure, is expressed within the myocardium and associates with cardiac fibrosis.

Publications

Tetranectin, a potential novel diagnostic biomarker of heart failure, is expressed within the myocardium and associates with cardiac fibrosis.

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