Abstract 74: The Role of Fibroblast-specific Canonical Tgfβ Signaling in Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hadi Khalil ◽  
Onur Kanisicak ◽  
Robert N. Correll ◽  
Michelle Sargent ◽  
Jeffery D. Molkentin
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Contractile Activity ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Type I ◽  
Tgfβ Signaling ◽  
Chronic Heart Disease

Heart failure is a progressive disease characterized by cardiomyocyte loss, interstitial fibrosis, and chamber remodeling. During physiological conditions cardiac fibroblasts contribute to the homeostatic maintenance of myocardial structure as well as the maintenance of biochemical, mechanical and electrical properties of the heart. Injury and/or cytokine stimulation activate fibroblasts which transdifferentiate into myofibroblasts. These newly formed cells secrete extracellular matrix (ECM) for wound healing and tissue remodeling through their contractile activity. Fibrosis mediated by these cells can initially be a beneficial response that acutely scarifies areas after an infarct to prevent wall rupture. However, during chronic disease states such as heart failure, persistent recruitment and activation of fibroblasts leads to excessive deposition of ECM that results in stiffening and pathological remodeling of the ventricles. During chronic heart disease, cardiomyocytes, immune cells and fibroblasts secrete the cytokine transforming growth factor-TGFβ, which activates fibroblasts and promotes their conversion to myofibroblasts. Manipulation of TGFβ by losartan, which antagonizes angiotensin II (AngII) and aspects of TGFβ signaling, has shown some anti-fibrotic effects in cardiovascular remodeling. Also deletion of Tgfbr1 (type I TGFβ receptor) in cardiomyocytes or a TGFβ blocking antibody reduced the fibrotic response after pressure overload. However heart failure was not improved because deleterious TGFβ signaling in fibroblasts persisted. We therefore utilized a novel fibroblast-specific inducible Cre-expressing mouse line (Periostin-MerCreMer) to examine the canonical (Smad2/3) TGFβ signaling within fibroblasts to determine how these cells and their activation mediate disease in heart failure. Our data indicate that fibroblast-specific deletion of Smad3 but not Smad2 was sufficient to significantly inhibit myocardial fibrosis. Smad2/3 double nulls were also generated and analyzed, as were TGFBR1 and TGFBR2 loxp targeted mice, also crossed with the Postn-MerCreMer knockin allele to achieve specificity in activated fibroblasts.

Abstract 275: The Role of Fibroblast-specific Canonical TGFβ Signaling in Cardiac Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Hadi Khalil
Keyword(s):  
Heart Failure ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Contractile Activity ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Type I ◽  
Tgfβ Signaling

Heart failure is a progressive disease characterized by cardiomyocyte loss, interstitial fibrosis, and chamber remodeling. During physiological conditions cardiac fibroblasts contribute to the homeostatic maintenance of myocardial structure as well as the maintenance of biochemical and electrical properties of the heart. Injury and/or cytokine stimulation activate fibroblasts which transdifferentiate into myofibroblasts. These newly formed cells secrete extracellular matrix (ECM) for wound healing and tissue remodeling through their contractile activity. Fibrosis mediated by these cells can initially be a beneficial response that acutely scarifies areas after an infarct to prevent wall rupture. However, during chronic disease states such as heart failure, persistent recruitment and activation of fibroblasts leads to excessive deposition of ECM that results in stiffening and pathological remodeling of the ventricles. During chronic heart disease, cardiomyocytes, immune cells and fibroblasts secrete the cytokine transforming growth factor-TGFβ, which activates fibroblasts and promotes their conversion to myofibroblasts. Previous work from Kass lab showed that manipulation of TGFβ by deletion of Tgfbr 1 (type I TGFβ receptor) in cardiomyocytes reduced the fibrotic response after pressure overload. However heart failure was not improved because deleterious TGFβ signaling in fibroblasts persisted. Here we utilized a novel myofibroblast-specific inducible Cre-expressing mouse line (Periostin-MerCreMer) to examine canonical (Smad2/3) TGFβ signaling to determine how these cells and their activation mediate disease in heart failure. Our data indicate that myofibroblast-specific deletion of Smad3 but not Smad2 was sufficient to significantly inhibit myocardial fibrosis after pressure overload, but not ultimately prevent it. Also, myofibroblast specific Smad2/3 double nulls and Tgfbr1/2 double nulls were generated and analyzed. Data from all these myofibroblast-specific mouse models with inhibited TGFβ signaling indicated that TGFβ initiates myofibroblast transformation and myocardial fibrosis with injury to the heart, but that ultimately other pathways can fully compensate and fibrosis eventually occurs.

scholarly journals The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

2021 ◽  
Vol 22 (4) ◽  
pp. 1861
Author(s):  
Jemima Seidenberg ◽  
Mara Stellato ◽  
Amela Hukara ◽  
Burkhard Ludewig ◽  
Karin Klingel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Beclin 1 ◽  
Type I ◽  
Alpha Smooth Muscle Actin

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

Abstract 292: TRPA1 Promoting Myofibroblast Differentiation Mediate Pressure Overload-Induced Cardiac Fibrosis

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Shuang Li ◽  
Dong Han ◽  
Dachun Yang
Keyword(s):  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Gene Transfection ◽  
Pressure Overload

Background: Hypertensive ventricular remodeling is a common cause of heart failure. Activation and accumulation of cardiac fibroblasts is the key contributors to this progression. Our previous studies indicate that transient receptor potential ankyrin 1 (TRPA1), a Ca 2+ channel necessary and sufficient, play a prominent role in ventricular remodeling. However, the molecular mechanisms regulating remain poorly understood. Methods: We used TRPA1 agonists cinnamaldehyde (CA) pretreatment and TRPA1 knockout mice to understand the role of TRPA1 in ventricular remodeling of hypertensive heart. We also examine the mechanisms through gene transfection and in vitro experiments. Results: TRPA1 overexpression fully activated myofibroblast transformation, while fibroblasts lacking TRPA1 were refractory to transforming growth factor β (TGF-β) -induced transdifferentiation. TRPA1 knockout mice showed hypertensive ventricular remodeling reversal following pressure overload. We found that the TGF-β induced TRPA1 expression through calcineurin-NFAT-Dyrk1A signaling pathway via the TRPA1 promoter. Once induced, TRPA1 activates the Ca 2+ -responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPA1-dependent transdifferentiation. Conclusion: Our study provides the first evidence that TRPA1 regulation in cardiac fibroblasts transformation in response to hypertensive stimulation. The results suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-β, Calcineurin, NFAT and Dyrk1A. Furthermore, these data indicate that negative modulation of cardiac fibroblast TRPA1 may represent a therapeutic strategy against hypertensive cardiac remodeling.

Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kevin Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Emily Mackey ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts

2015 ◽  
Vol 309 (3) ◽  
pp. H512-H522 ◽  
Author(s):  
Kiyoshi Yamagami ◽  
Toru Oka ◽  
Qi Wang ◽  
Takamaru Ishizu ◽  
Jong-Kook Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Vascular Permeability ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Chronic Phase ◽  
Vehicle Group

Although cardiac fibrosis causes heart failure, its molecular mechanisms remain elusive. In this study, we investigated the mechanisms of cardiac fibrosis and examined the effects of the antifibrotic drug pirfenidone (PFD) on chronic heart failure. To understand the responsible mechanisms, we generated an in vivo pressure-overloaded heart failure model via transverse aortic constriction (TAC) and examined the effects of PFD on chronic-phase cardiac fibrosis and function. In the vehicle group, contractile dysfunction and left ventricle fibrosis progressed further from 4 to 8 wk after TAC but were prevented by PFD treatment beginning 4 wk after TAC. We isolated cardiac fibroblasts and vascular endothelial cells from the left ventricles of adult male mice and investigated the cell-type-specific effects of PFD. Transforming growth factor-β induced upregulated collagen 1 expression via p38 phosphorylation and downregulated claudin 5 (Cldn5) expression in cardiac fibroblasts and endothelial cells, respectively; both processes were inhibited by PFD. Moreover, PFD inhibited changes in the collagen 1 and Cldn5 expression levels, resulting in reduced fibrosis and serum albumin leakage into the interstitial space during the chronic phase in TAC hearts. In conclusion, PFD inhibited cardiac fibrosis by suppressing both collagen expression and the increased vascular permeability induced by pressure overload.

scholarly journals The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation

2021 ◽  
Author(s):  
Nicholas W. Chavkin ◽  
Soichi Sano ◽  
Ying Wang ◽  
Kosei Oshima ◽  
Hayato Ogawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Planar Cell Polarity ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
Orphan Receptor ◽  
Myofibroblast Differentiation ◽  
Cultured Fibroblasts

AbstractBackgroundA hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early pro-inflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation.Methods and ResultsThe role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction (TAC) surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after TAC surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2-KO mice displayed a pro-inflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, TAC surgery led to the death of all mice by day 6 that was associated with myocardial hyper-inflammation and vascular leakage.ConclusionsTogether, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.

scholarly journals A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Weijiang Tan ◽  
Xiang Li ◽  
Shuang Zheng ◽  
Xiaohui Li ◽  
Xiaoshen Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Pathological Examination ◽  
Type I ◽  
Preserved Ejection Fraction

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chronic pressure overload in the left ventricles of Tibetan minipigs for 12 weeks. Cardiac function, pathological and cellular changes, fibrotic signaling activation, and gene expression profiles were explored. The left ventricles developed concentric hypertrophy from weeks 4 to 6 and transition to dilation starting in week 10. Notably, the left ventricular ejection fraction was maintained at >50% in the DAC group during the 12-week period. Pathological examination, biochemical analyses, and gene profile analysis revealed evidence of inflammation, fibrosis, cell death, and myofilament dephosphorylation in the myocardium of HFpEF model animals, together with gene expression shifts promoting cardiac remodeling and downregulating metabolic pathways. Furthermore, we noted the activation of several signaling proteins that impact cardiac fibrosis and remodeling, including transforming growth factor-β/SMAD family members 2/3, type I/III/V collagens, phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, matrix metalloproteinases 2 and 9, tissue inhibitor of metalloproteinases 1 and 2, interleukins 6 and 1β, and inhibitor of κBα/nuclear factor-κB. Our findings demonstrate that this chronic pressure overload-induced porcine HFpEF model is a powerful tool to elucidate the mechanisms of this disease and translate preclinical findings.

P5001Acute cardiac fibrogenic response triggered by endotrophin, a type VI collagen signalling molecule

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A L Reese-Petersen ◽  
M Karsdal ◽  
F Genovese
Keyword(s):  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Cardiac Fibroblasts ◽  
Vehicle Control ◽  
Serum Starvation ◽  
Type I ◽  
Type Vi Collagen ◽  
Ecm Proteins

Abstract Background/Aim Accumulation of extracellular matrix (ECM) proteins is the hallmark of cardiac fibrosis, causing stiffening of the ventricular wall, which can lead to heart failure and ultimately death. Many different cell types and growth factors are involved in this process but fibroblasts are the main source of ECM proteins. Here we present results from an in vitro model indicating that endotrophin (ETP), a collagen type VI fragment, activates cardiac fibroblasts and induces fibrogenesis. Methods The effect of ETP, transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF)-DD on ECM protein synthesis was assessed in a scar-in-a-jar (SiaJ) cell model using human cardiac fibroblasts isolated from the atrium of an adult healthy donor. Cells were seeded in 48-well plates at a density of 30.000 cells/well and incubated for 24H in Dulbecco's Modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS). Serum starvation was done by seeding the cells for further 24H in DMEM + 0.4% FBS. Fresh medium was added at day 0 with 37.5/25mg/mL Ficoll 70/400 and 1% ascorbic acid, containing 11.75 nM human recombinant ETP, 0.04 nM TGF-β, 0.39 nM PDGF-DD or a vehicle control. Medium was changed and collected at day 3 and 6. Biomarkers of type I (PRO-C1), III (PRO-C3), VI (PRO-C6) collagens and fibronectin (FBN-C) formation were assessed in the medium by ELISAs developed at Nordic Bioscience. Results ETP induced a significant increase in PRO-C1, PRO-C3 and FBN-C (comparable to TGF-β and PDGF-DD) within the first three days of the experiment, compared to the vehicle control. The levels remained significantly increased for PRO-C3 and FBN-C throughout the experiment, and non-significantly elevated for PRO-C1, compared to the vehicle control. PDGF-DD significantly induced synthesis of type VI collagen compared to the vehicle control, while TGF-β induced a small increase in synthesis from day 0–3, after which it seemed to inhibit synthesis. Conclusion For the first time, a direct pro-fibrotic effect on fibroblasts induced by ETP has been shown. This novel pathway of activation could play an important role in regulating cardiac fibrosis, and thus prove to be a therapeutic target. This SiaJ model in combination with the investigated biomarkers of ECM formation could be used to further elucidate the mechanisms behind cardiac fibrosis.

Abstract 230: Cartilage Intermediate Layer Protein-1 Attenuates Pressure Overload-induced Cardiac Fibrosis by Targeting Transforming Growth Factor-β1

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Li Li ◽  
Cheng-Lin Zhang ◽  
Dan Wu ◽  
Li-Ling Wu
Keyword(s):  
Growth Factor ◽  
Intermediate Layer ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Transforming Growth Factor Β1 ◽  
Tgf Β1

Background: Cartilage intermediate layer protein-1 (CILP-1), a monomeric extracellular matrix glycoprotein expressed mainly in the middle zones of articular cartilage, interacts directly with transforming growth factor-β1 (TGF-β1). Recent studies showed that CILP-1 was upregulated in the heart tissue following cardiac ischemia reperfusion injury. However, the role of CILP-1 in pathological cardiac remodeling is poorly defined. Aims: To explore the effect of CILP-1 on myocardial interstitial fibrosis and reveal the possible molecular mechanism. Methods and Results: We found that CILP-1 was mainly expressed in mouse cardiac fibroblasts (CFs) by using western blot analysis and immunofluorescence. Myocardial expression of CILP-1 was upregulated in mice subjected to transverse aortic constriction (TAC) for 2, 4, and 8 weeks. AAV-9-mediated delivery of CILP-1 into mice increased the binding of CILP-1 with TGF-β1, attenuated interstitial fibrosis, and improved cardiac function. In cultured adult mouse CFs, CILP-1 overexpression inhibited myofibroblast differentiation and expression of profibrotic molecules induced by TGF-β1. Furthermore, CILP-1 attenuated TGF-β1-induced Smad3 phosphorylation and nuclear translocation. Conclusions: CILP-1 alleviates pressure overload-induced cardiac fibrosis and dysfunction. CILP-1 exerts its anti-fibrotic effect through targeting TGF-β1 signaling. This study will offer a new therapeutic strategy for preventing and treating myocardial interstitial remodeling.

Abstract 95: The Role of TGFβ Signaling in a Fibrotic cMyBP-C HCM/HF Model

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Qinghang Meng ◽  
Bidur Bhandary ◽  
Md. Shenuarin Bhuiyan ◽  
Hanna Osinska ◽  
Jeffrey Robbins
Keyword(s):  
Transgenic Mice ◽  
Life Span ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Gene Encoding ◽  
Western Blots

Purpose: Hypertrophic cardiomyopathy (HCM) is considered one of the most common genetic heart disorders with a prevalence of about 1 in 500 people, with 35% of those affected being attributed to mutations within the gene encoding cardiac myosin-binding protein C (cMyBP-C). Cardiac stress, as well as cMyBP-C mutations, can trigger production of a 40kDa truncated fragment derived from the amino terminus of cMyBP-C. Genetic expression of this 40kDa fragment in mouse cardiomyocytes ( Mybp3 40kDa ) leads to HCM, fibrosis and heart failure, mimicking human disease progression. The transforming growth factor-β (TGFβ) signaling pathway has been implicated in a variety of fibrotic processes. The goal of this study is to define the role of TGFβ signaling in distinct cell populations, the cardiomyocyte and fibroblast, in the cMyBP-C HCM/HF model. Methods and results: Masson’s Trichrome staining, PCR arrays, immunohistochemistry and western blots were performed to characterize the fibrotic progression in Mybp3 40kDa transgenic mice. Cardiac fibrosis was initially detected 4 weeks after transgene expression. Extensive interstitial fibrosis and severe atrial fibrosis were detected at 16 weeks. Both canonical and non-canonical TGFβ pathways were active during fibrotic progression. To specifically block TGFβ signaling in Mybp3 40kDa transgenic mice, compound mutant mice were generated, in which the tgfbr1 or tgfbr2 alleles were ablated, either in cardiomyocytes or in activated fibroblasts (myofibroblasts) by αMHC-Cre or Periostin-MerCreMer-Cre respectively. Blockage of TGFβ signaling in either cardiomyocytes or myofibroblasts alleviated cardiac fibrosis. Furthermore, treatment with the non-canonical TGFβ signaling inhibitor MMI-0100 also alleviated cardiac fibrosis and increased the life span of the Mybp3 40kDa transgenic mice. Conclusions: TGFβ signaling is activated in the Mybp3 40kD HCM/HF model. Genetic or pharmaceutical inhibition of TGFβ signaling inhibited fibrosis and increased the life span in this model.

Sign in / Sign up

Export Citation Format

Share Document