Increased serotonin (5HT) concentration and signaling, can lead to pathological remodeling of the cardiac valves. We previously showed that a reduction of the 5HT transporter (SERT) expression in the mitral valve (MV) contributes to the progression of degenerative MV regurgitation (MR). We sought to investigate the myocardial and valvular phenotype of SERT-/- mice in order to identify remodeling mechanisms specific to the MV and left ventricular (LV) remodeling. Using 8- and 16-week-old WT and SERT-/- mice we show that male and female animals deficient of SERT have pathological remodeling of the cardiac valves, myocardial fibrosis, diminished ejection fraction and altered left ventricular dimensions. In the MV and intervalvular area of the aortic valve (AV)-MV, gene expression, including Col1a1 mRNA, was progressively altered with age up until 16 weeks of age. In contrast, in the AV and myocardium, most gene expression changes occurred earlier and plateaued by 8 weeks. To explore basal differences in susceptibility to remodeling stimuli among cardiac valves, valve interstitial cells (VIC) were isolated from AV, MV, tricuspid valve (TV), pulmonary valve (PV) and fibroblasts (Fb) from the myocardial apex from 16 weeks old wild type (WT) mice. After 24h stimulation with 10μM of 5HT, the gene expression of Col1a1 and Acta2 were upregulated in MVIC to a higher degree than in VIC from other valves and Fb. Treatment with TGFβ1 similarly upregulated Cola1 and Acta2 in MVIC and AVIC, while the increase was milder in right heart VIC and Fb. Experiments were also carried out with human VIC. In comparison to mice, human left heart VIC were more sensitive to 5HT and TGFβ1, upregulating COL1A1 and ACTA2; TGFβ1 upregulated HTR2B expression in all VIC. Our results support the hypothesis that a deleterious cardiac effect of SERT downregulation may be mediated by increased susceptibility to HTR2B-dependent pro-fibrotic mechanisms, which are distinct among VIC populations and cardiac fibroblasts, regardless of SERT activity. Given that HTR2B mechanisms involved in VIC and myocardial remodeling response are due to both 5HT and also to downstream related TGFβ1 and TNFα activity, targeting HTR2B could be a therapeutic strategy for dual treatment of MR and LV remodeling.

UNASSIGNED: The combination of a high fructose and high salt diet typical of western diet induces high blood pressure, aortic stiffening, left ventricular (LV) diastolic dysfunction and impaired renal function in rodents. Despite an activated renin-angiotensin system (RAS) in rats fed high fructose and high salt, acute inhibition of the RAS pathway does not improve cardiac and vascular parameters. It may well be that longer term treatment is required to permit remodeling and improve cardiovascular function. Thus, we hypothesized that chronic RAS inhibition fructose+high salt-fed rats to restore blood pressure (BP) to levels similar to glucose plus normal salt-fed controls will improve cardiorenal function and histopathology.
UNASSIGNED: Male and female Sprague Dawley rats monitored by hemodynamic telemetry were fed 0.4% NaCl chow during baseline, then changed to chow containing either 20% glucose+0.4% NaCl (G) or 20% fructose+4% NaCl (F) and treated with vehicle, enalapril (Enal, 4 mg/kg/d) or losartan (Los, 8 mg/kg/d) by osmotic minipump for 25-26 days.
UNASSIGNED: BP was elevated in the fructose+high salt groups of both sexes (P < 0.05) and restored to control levels by Enal or Los. Pulse wave velocity (PWV) was lower in female F+Los rats and cardiac output higher in female F+Enal rats. GFR was not changed by diet or treatment. Fructose+high salt groups of both sexes displayed higher albuminuria that was decreased by Enal in male rats. Cardiac fibrosis and mesangial hypercellularity were greater in fructose+high salt-fed rats of both sexes and improved with either Los or Enal.
UNASSIGNED: Thus, inhibition of the RAS improves early changes in cardiac and renal histopathology in both sexes and albuminuria in male rats fed high fructose and high salt diet. Functional improvements in cardiorenal parameters may require longer treatment.

Histone deacetylase 6 (HDAC6) belongs to the class IIb group of the histone deacetylase family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of HDAC6 in cardiac remodelling post-infarction. Experimental myocardial infarction (MI) was created in HDAC6-deficient (HDAC6-/-) mice and wild-type (HADC6+/+) by left coronary artery ligation. At days 0 and 14 post-MI, we evaluated cardiac function, morphology and molecular endpoints of repair and remodelling. At day 14 after surgery, the ischemic myocardium had increased levels of HADC6 gene and protein of post-MI mice compared to the non-ischemic myocardium of control mice. As compared with HDAC6-/--MI mice, HADC6 deletion markedly improved infarct size and cardiac fibrosis as well as impaired left ventricular ejection fraction and left ventricular fraction shortening. At the molecular levels, HDAC6-/- resulted in a significant reduction in the levels of the transforming growth factor-beta 1 (TGF-β1), phosphor-Smad-2/3, collagen I and collagen III proteins and/or in the ischemic cardiac tissues. All of these beneficial effects were reproduced by a pharmacological inhibition of HADC6 in vivo. In vitro, hypoxic stress increased the expressions of HADC6 and collagen I and III gene; these alterations were significantly prevented by the HADC6 silencing and TubA loading. These findings indicated that HADC6 deficiency resists ischemic injury by a reduction of TGF-β1/Smad2/3 signalling activation, leading to decreased extracellular matrix production, which reduces cardiac fibrosis and dysfunction, providing a potential molecular target in the treatment of patients with MI.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized with progressive cardiac fibrosis and heart failure. However, the exact mechanism driving the progression of cardiac fibrosis and heart failure in ACM remains elusive. This study aims to investigate the underlying mechanisms of progressive cardiac fibrosis in ACM caused by newly identified Desmoglein-2 (DSG2) variation.
METHODS: We identified homozygous DSG2F531C variant in a family with 8 ACM patients using whole-exome sequencing and generated Dsg2F536C knock-in mice. Neonatal and adult mouse ventricular myocytes isolated from Dsg2F536C knock-in mice were used. We performed functional, transcriptomic and mass spectrometry analyses to evaluate the mechanisms of ACM caused by DSG2F531C variant.
RESULTS: All eight patients with ACM were homozygous for DSG2F531C variant. Dsg2F536C/F536C mice displayed cardiac enlargement, dysfunction, and progressive cardiac fibrosis in both ventricles. Mechanistic investigations revealed that the variant DSG2-F536C protein underwent misfolding, leading to its recognition by BiP within the endoplasmic reticulum, which triggered endoplasmic reticulum stress, activated the PERK-ATF4 signaling pathway and increased ATF4 levels in cardiomyocytes. Increased ATF4 facilitated the expression of TGF-β1 in cardiomyocytes, thereby activating cardiac fibroblasts through paracrine signaling and ultimately promoting cardiac fibrosis in Dsg2F536C/F536C mice. Notably, inhibition of the PERK-ATF4 signaling attenuated progressive cardiac fibrosis and cardiac systolic dysfunction in Dsg2F536C/F536C mice.
CONCLUSIONS: Hyperactivation of the ATF4/TGF-β1 signaling in cardiomyocytes emerges as a novel mechanism underlying progressive cardiac fibrosis in ACM. Targeting the ATF4/TGF-β1 signaling may be a novel therapeutic target for managing ACM.

Coronary heart disease, hypertension, myocarditis, and valvular disease cause myocardial fibrosis, leading to heart enlargement, heart failure, heart rate failure, arrhythmia, and premature ventricular beat, even defibrillation can increase the risk of sudden death. Although cardiac fibrosis is common and widespread, there are still no effective drugs to provide adequate clinical intervention for cardiac fibrosis. In this review article, we classify the compounds for treating cardiac fibrosis into natural products, synthetic compounds, and patent drugs according to their sources. Additionally, the structures, activities and signaling pathways of these compounds are discussed. This review provides insight and could provide a reference for the design of new anti-cardiac fibrosis compounds and the new use of older drugs.

OBJECTIVE: Cardiac fibrosis is characterized by aberrant collagen deposition in the heart. Macrophage polarization or infiltration is the main reason to accelerate the collagen deposition. We attempted to investigate the involvement of MKL1 in macrophages during the development of cardiac fibrosis.
METHODS: Cardiac fibrosis is induced by myocardial infarction (MI). The MKL1f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1ΔN200-Rosa26 mice.
RESULTS: MKL1 expression was significantly increased in macrophages of both ischemic cardiomyopathy (ICM) patients and mice induced to develop myocardial infarction. Deletion of MKL1 in macrophages improved the heart function after MI-induced cardiac fibrosis. Consistently, MKL1Mϕ-OE mice displayed more severe cardiac fibrosis and worsened heart function than the control mice after MI. Moreover, administration of a small-molecule MKL1 inhibitor CCG-1423 also decreased the collagen deposition after MI.
CONCLUSIONS: Our data demonstrate that MKL1 in macrophages contributes to cardiac fibrosis pathogenesis and reinforce the notion that targeting MKL1 may yield effective antifibrotic therapeutics in the heart.

[This corrects the article DOI: 10.3389/fcvm.2023.1223244.].

UNASSIGNED: Cardiac fibrosis is increasingly recognized as a marker of worse outcomes in long-term follow-up after heart transplantation (HTX). We investigated the clinical determinants and biomarkers of focal and interstitial cardiac fibrosis as assessed with cardiac magnetic resonance (CMR).
UNASSIGNED: Consecutive HTX recipients underwent CMR with late gadolinium enhancement for focal myocardial fibrosis and T1 mapping for interstitial fibrosis. We calculated the correlations of these findings with clinical parameters, history, biomarkers of fibrosis (B-type natriuretic peptide (BNP), growth differentiation factor-15, galectin-3 and soluble ligand ST2) and echocardiography.
UNASSIGNED: Forty-eight HTX patients were included: median age 63 ± 13 years, 11 ± 6 years after heart transplantation. Only donor weight (p 0.044) and the rate of a > 30 % mismatch between donor and recipient weight (p 0.02) were significantly different in patients with vs. without late LGE. Extracellular volume (ECV) was correlated with the weight mismatch between donor and recipient (r = 0.32, p 0.04), resulting in a higher ECV for oversized donors. BNP was the only biomarker of the four studied that was correlated with interstitial fibrosis as assessed by ECV (r = 0.35, p 0.04). T1 relaxation time was correlated with treated acute cellular rejection grade ≥ 2 (ISHLT grading) (r = 0.34, p 0.02).
UNASSIGNED: Both focal and interstitial fibrosis, as determined by CMR, after heart transplantation are correlated with donor and recipient weight mismatch. BNP was the only biomarker clinically relevant to interstitial cardiac fibrosis.

This study aimed to evaluate the effects of ursolic acid (UA) on Angiotensin II (Ang II)-treated neonatal rat cardiac fibroblasts (rCFs) as an in vitro model of cardiac fibrosis. The rCFs were isolated from two-day-old neonatal rats. An in vitro model of cardiac fibrosis was established using 500 nm Ang II treatment for 48 h. The cells were then treated with 5 and 10 μM of UA for 24 and 48 h. Masson\'s trichrome staining, hydroxyproline content assay, scratch assay, apoptosis assay, measurements of superoxide dismutase (SOD) and malondialdehyde (MDA) levels, real-time PCR, immunocytology and western blotting, were employed to assess the impact of UA. Ang II induced fibrosis in rCFs, as evidenced by the examination of various fibrotic markers. Upon treatment with 5 and 10 μM of UA, the amount of fibrosis in Ang II-treated rCFs was significantly decreased, so that the hydroxyproline concentration was reduced to 0.3 and 0.7 times, respectively. The RNA expression of the Col1a1, Col3a1, Tgfb1, Acta2 and Mmp2 genes had a decrease as well as Nrf2 and HO-1 had an increase after UA treatment. UA could lessen the harmful effects of cardiac fibrosis in a dose- and time-dependent manner, due to its antiapoptotic, antioxidant and cardioprotective properties. This suggests the potential of UA for treatment of cardiac fibrosis.

Fibrosis, a pathological increase in extracellular matrix proteins, is a significant health issue that hinders the function of many organs in the body, in some cases fatally. In the heart, fibrosis impacts on electrical propagation in a complex and poorly predictable fashion, potentially serving as a substrate for dangerous arrhythmias. Individual risk depends on the spatial manifestation of fibrotic tissue, and learning the spatial arrangement on the fine scale in order to predict these impacts still relies upon invasive ex vivo procedures. As a result, the effects of spatial variability on the symptomatic impact of cardiac fibrosis remain poorly understood. In this work, we address the issue of availability of such imaging data via a computational methodology for generating new realisations of cardiac fibrosis microstructure. Using the Perlin noise technique from computer graphics, together with an automated calibration process that requires only a single training image, we demonstrate successful capture of collagen texturing in four types of fibrosis microstructure observed in histological sections. We then use this generator to quantitatively analyse the conductive properties of these different types of cardiac fibrosis, as well as produce three-dimensional realisations of histologically-observed patterning. Owing to the generator\'s flexibility and automated calibration process, we also anticipate that it might be useful in producing additional realisations of other physiological structures.