Pathophysiological mechanism and therapeutic role of S100 proteins in cardiac failure: a systematic review. Imbalzano Egidio,Mandraffino Giuseppe,Casciaro Marco,Quartuccio Sebastiano,Saitta Antonino,Gangemi Sebastiano Heart failure reviews S100 proteins are a family of highly acidic calcium-binding proteins involved in calcium handling in many tissues and organs. Some of these proteins are highly expressed in cardiac tissue, and an impairment of some specific S100 proteins has been related to heart failure. To check this hypothesis, we decided to review the literature since 2008 until May 2015. According to the studies collected, recovering S100A1 levels may enhance contractile/relaxing performance in heart failure, reverse negative force-frequency relationship, improve contractile reserve, reverse diastolic dysfunction and protect against pro-arrhythmic reductions of sarcoplasmic reticulum calcium. The safety profile of gene therapy was also confirmed. Increased S100B protein levels were related to a worse outcome in chronic heart failure. S100A8/A9 complex plasma levels, as well as other inflammatory biomarkers, were significantly higher in chronic heart failure patients. S100A2 seems to increase both contractile and relaxation performance in animal cardiomyocytes. Otherwise, S100A6 cardiac expression seems to have no effects on contractility. S100A4 KO mice showed reduced cardiac interstitial fibrosis. Data collected encourage a potential prospective application in human. These proteins could be exploited as biomarkers in stadiation and prognosis of chronic heart failure, as well as therapeutic target to rescue failing heart. Registration details The study protocol has been registered in PROSPERO ( http://www.crd.york.ac.uk/PROSPERO/ ) under registration number CRD42015027932. 10.1007/s10741-016-9529-8

Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts. Tamaki Yodo,Iwanaga Yoshitaka,Niizuma Shinichiro,Kawashima Tsuneaki,Kato Takao,Inuzuka Yasutaka,Horie Takahiro,Morooka Hanako,Takase Toru,Akahashi Yasumitsu,Kobuke Kazuhiro,Ono Koh,Shioi Tetsuo,Sheikh Søren P,Ambartsumian Noona,Lukanidin Eugene,Koshimizu Taka-Aki,Miyazaki Shunichi,Kimura Takeshi Journal of molecular and cellular cardiology Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53-downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53-associated genes. These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis. 10.1016/j.yjmcc.2013.01.007

A pilot study of S100A4, S100A8/A9, and S100A12 in dilated cardiomyopathy: novel biomarkers for diagnosis or prognosis? ESC heart failure AIMS:Circulating biomarkers can provide important information for the diagnosis and prognosis of dilated cardiomyopathy (DCM). We explored novel biomarkers for the diagnosis and prognosis of DCM to improve clinical decision-making. METHODS AND RESULTS:A total of 238 DCM patients and 65 control were consecutively enrolled at Zhongshan Hospital between January 2017 and January 2019. In the screening set, four DCM patients and four controls underwent measurements of serum proteomic analysis. Seventy-six differentially expressed circulating proteins were screened by data-independent acquisition proteomics, and three of these proteins (S100A4, S100A8/A9, and S100A12) were validated by multiple-reaction monitoring-mass spectrometry. In the validation set, subsequently, a total of 234 DCM patients and 61 control subjects were evaluated by enzyme-linked immunosorbent assay. Circulating S100A4, S100A8/A9, and S100A12 were significantly increased in DCM patients (P < 0.001). These three proteins were significant positively correlated with other parameters, such as Lg (NT-proBNP), IL-1β, TGF-β, CRP, left ventricular end-diastolic diameter, and left ventricular end-systolic diameter, whereas they were negatively correlated with left ventricular ejection fraction, respectively (P < 0.05). The receiver operator characteristic curve showed the combination of S100A4, S100A8/A9, and S100A12 [area under curve (AUC) 0.88, 95% confidence interval (CI) 0.84-0.93] was better than single S100A4 (AUC 0.74, 95% CI 0.68-0.81), S100A8/A9 (AUC 0.82, 95% CI 0.77-0.88), or S100A12 (AUC 0.80, 95% CI 0.72-0.88) in the diagnosis of DCM (P < 0.01). After a median follow-up period of 33.5 months, 110 patients (47.01%) experienced major adverse cardiac events (MACEs), including 46 who had cardiac deaths and 64 who had heart failure rehospitalizations. Kaplan-Meier analysis indicated that the DCM patients with ≥75th percentile level of S100A4 had a significantly higher incidence of MACEs than those with <75th percentile level of S100A4 (61.40% vs. 42.37%, P < 0.05). There were no significant differences of MACE rate among DCM patients with different concentrations of S100A8/A9 and S100A12 (P > 0.05). Cox proportional hazards regression analysis revealed that S100A4 [≥75th percentile vs. <75th percentile: hazard ratio (HR) 1.65; 95% CI 1.11-2.45] remained significant independent predictors for MACEs (P < 0.05); however, S100A8/A9 and S100A12 were not independent factors for predicting MACE (P ≥ 0.05). CONCLUSIONS:S100A4, S100A8/A9, and S100A12 may be additional diagnostic tools for human DCM recognition, and the combination of these three indicators helped to improve the accuracy of a single index to diagnose DCM. Additionally, S100A4 was identified as a significant predictor of prognosis in patients with DCM. 10.1002/ehf2.14605

Murine neonatal cardiac B cells promote cardiomyocyte proliferation and heart regeneration. NPJ Regenerative medicine The irreversible loss of cardiomyocytes in the adult heart following cardiac injury leads to adverse cardiac remodeling and ventricular dysfunction. However, the role of B cells in cardiomyocyte proliferation and heart regeneration has not been clarified. Here, we found that the neonatal mice with B cell depletion showed markedly reduced cardiomyocyte proliferation, leading to cardiac dysfunction, fibrosis scar formation, and the complete failure of heart regeneration after apical resection. B cell depletion also significantly impaired heart regeneration and cardiac function in neonatal mice following myocardial infarction (MI). However, B cell depletion in adult mice suppressed tissue inflammation, inhibited myocardial fibrosis, and improved cardiac function after MI. Interestingly, B cell depletion partially restricted cardiomyocyte proliferation in adult mice post-MI. Single-cell RNA sequencing showed that cardiac B cells possessed a more powerful ability to inhibit inflammatory responses and enhance angiogenesis in the postnatal day 1 (P1) mice compared with P7 and adult mice. Besides, the proportion of cardioprotective B cell clusters with high expression levels of S100a6 (S100 calcium-binding protein A6) and S100a4 (S100 calcium-binding protein A4) was greatly decreased in adult heart tissues compared with neonatal mice after cardiac damage. Thus, our study discovers that cardiac B cells in neonatal mice are required for cardiomyocyte proliferation and heart regeneration, while adult B cells promote inflammation and impair cardiac function after myocardial injury. 10.1038/s41536-023-00282-7

Circulating S100A4 as a prognostic biomarker for patients with nonparoxysmal atrial fibrillation after catheter ablation. Annals of translational medicine BACKGROUND:Atrial fibrosis is involved in non-paroxysmal atrial fibrillation (NPAF) and is mainly mediated by the calcium-binding protein S100A4. This study aimed to verify the role of circulating S100A4 in the diagnosis of atrial fibrosis and the prognosis of NPAF. METHODS:Consecutive NPAF patients undergoing catheter ablation were selected. Patients with low voltage amplitudes (<0.40 mV) in the left atrium (LA), defined as low voltage zones (LVZs), were grouped in the scar group by electroanatomic mapping (EAM). Circulating S100A4 was detected by a human enzyme-linked immunosorbent assay (ELISA). The role of S100A4 in atrial fibrosis was further evaluated by Masson's trichrome staining and immunochemistry (IHC) in NPAF (atrial pacing) and control dogs. The prognostic value of the circulating S100A4 was evaluated by Cox regression analyses, the Kaplan-Meier (KM) method, and receiver operating characteristic (ROC) curves. RESULTS:We enrolled a total of 101 NPAF patients (age 60±8 years) who underwent EAM, including 53 patients with scars and 48 patients without scars at 1-year follow-up. The scar group showed a higher serum level of S100A4 (3.4±1.7 . 2.5±1.4 ng/mL, P<0.001) than the non-scar group. In the canine model, scar size matched the larger location of interstitial fibrosis in the NPAF group determined by Masson's trichrome staining. The expression of α-SMA and S100A4 was elevated in the NPAF group as determined by IHC compared to the control group (P<0.001). The clinical recurrence rate was markedly elevated in the scar group (27.1% . 8.9%, P<0.001), and the area under the ROC curve was high (0.865, 95% CI: 0.750-0.981) in predicting clinical recurrence of NPAF with the circulating S100A4 model. CONCLUSIONS:Circulating S100A4 plays a role in atrial fibrosis in NPAF patients following ablation. The level of serum S100A4 can predict the clinical recurrence of NPAF. 10.21037/atm-21-1101