Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis

2014 ◽  
Vol 127 (7) ◽  
pp. 435-448 ◽  
Author(s):  
Zhi Zeng ◽  
Liang Shen ◽  
Xixian Li ◽  
Tao Luo ◽  
Xuan Wei ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Down Regulation ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Mitochondrial Permeability ◽  
Myocardial Apoptosis ◽  
Heart Failure Progression

In the present study, we have shown that H2R deficiency or blockade could reduce cardiac fibrosis through the down-regulation of calcineurin expression in cardiac fibroblasts and reduce myocardial apoptosis through lowering of mitochondrial permeability in cardiomyocytes, finally achieving the goal of improving heart failure.

scholarly journals EPRS Regulates Proline-rich Pro-fibrotic Protein Synthesis during Cardiac Fibrosis

2019 ◽  
Author(s):  
Jiangbin Wu ◽  
Kadiam C Venkata Subbaiah ◽  
Li Huitong Xie ◽  
Feng Jiang ◽  
Deanne Mickelsen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Translational Control ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Mrna Translation ◽  
Trna Synthetase ◽  
Mouse Heart ◽  
List Type ◽  
Human And Mouse

AbstractRationaleIncreased protein synthesis of pro-fibrotic genes is a common feature of cardiac fibrosis, a major manifestation of heart failure. Despite this important observation, critical factors and molecular mechanisms for translational control of pro-fibrotic genes during cardiac fibrosis remain unclear.ObjectiveThis study aimed to test the hypothesis that cardiac stress-induced expression of a bifunctional aminoacyl-tRNA synthetase (ARS), glutamyl-prolyl-tRNA synthetase (EPRS), is preferentially required for the translation of proline codon-rich (PRR) pro-fibrotic mRNAs in cardiac fibroblasts during cardiac fibrosis.Methods and ResultsBy analyses of multiple available unbiased large-scale screening datasets of human and mouse heart failure, we have discovered that EPRS acts as an integrated node among all the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at both mRNA and protein level (∼1.5-2.5 fold increase) in failing hearts compared with non-failing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele of Eprs globally (Eprs+/-) using CRISPR-Cas9 technology or in a myofibroblast-specific manner (Eprsflox/+; PostnMCM/+) strongly reduces cardiac fibrosis (∼50% reduction) in isoproterenol- and transverse aortic constriction-induced heart failure mouse models. Inhibition of EPRS by a prolyl-tRNA synthetase (PRS)-specific inhibitor, halofuginone (Halo), significantly decreased the translation efficiency of proline-rich collagens in cardiac fibroblasts. Furthermore, using transcriptome-wide RNA-Seq and polysome profiling-Seq in Halo-treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 and Sulf1, which are translationally regulated by EPRS. As a major EPRS downstream effector, SULF1 is highly enriched in human and mouse myofibroblast. siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition.ConclusionsOur results indicate that EPRS preferentially controls the translational activation of proline codon-rich pro-fibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling.Novelty and SignificanceWhat is known?TGF-β and IL-11 increase synthesis of pro-fibrotic proteins during cardiac fibrosis.Many pro-fibrotic genes contain Pro genetic codon rich motifs such as collagens.EPRS is an essential house-keeping enzyme required for ligating Pro to tRNAPro for the synthesis of Pro-containing proteins.What New Information Does This Article Contribute?This study is a pioneering investigation of translational control mechanisms of pro-fibrotic gene expression in cardiac fibrosis.EPRS mRNA and protein expression are induced in failing human hearts and mouse hearts undergoing pathological cardiac remodeling.The first demonstration of the in vivo function of EPRS in cardiac remodeling. Heterozygous Eprs global knockout and myofibroblast-specific tamoxifen-inducible Eprs conditional knockout mice show reduced pathological cardiac fibrosis under stress, suggesting that the reduction of EPRS is cardioprotective.Identification of novel preferential translational target genes of EPRS. We found that EPRS regulates translation of Pro-rich (PRR) transcripts, which comprise most of the ECM and secretory signaling molecules. Among those targets, we identified multiple novel PRR genes such as LTBP2 and SULF1.SULF1 is validated as a myofibroblast marker protein in human and mouse heart failure and a potential anti-fibrosis target gene.In cardiac fibroblasts, the synthesis of pro-fibrotic proteins is upregulated by cardiac stressors to activate extracellular matrix deposition and impair cardiac function. In this study, we have discovered an EPRS-PRR gene axis that influences translational homeostasis of pro-fibrotic proteins and promotes pathological cardiac remodeling and fibrosis. EPRS is identified as a common node downstream of multiple cardiac stressors and a novel regulatory factor that facilitates pro-fibrotic mRNA translation in cardiac fibrosis. Global and myofibroblast-specific genetic ablation of EPRS can effectively reduce cardiac fibrosis. This study reveals a novel translational control mechanism that modulates cardiac fibrosis and heart function. Mild inhibition of PRR mRNA translation could be a general therapeutic strategy for the treatment of heart disease. These findings provide novel insights into the translational control mechanisms of cardiac fibrosis and will promote the development of novel therapeutics by inhibiting pro-fibrotic translation factors or their downstream effectors.

scholarly journals Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure

Circulation ◽  
2018 ◽  
Vol 138 (5) ◽  
pp. 513-526 ◽  
Author(s):  
Kevin J. Morine ◽  
Xiaoying Qiao ◽  
Sam York ◽  
Peter S. Natov ◽  
Vikram Paruchuri ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Human Subjects ◽  
Lv Function ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Bone Morphogenetic Protein 9 ◽  
Human Cardiac Fibroblasts ◽  
Tgf Β1

Background: Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-β1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFβ coreceptor that promotes TGF-β1 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.

Abstract 13837: Adrenergic Receptors β2 and β3 Transduce Differential Signals in Cardiac Fibroblasts

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kota Tonegawa ◽  
Hiroyuki Nakayama ◽  
Hiromi Igarashi ◽  
Sachi Matsunami ◽  
Nao Hayamizu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cell Types ◽  
Neonatal Rat ◽  
Rt Pcr ◽  
Β Blocker ◽  
Selective Agonists ◽  
Selective Blocker ◽  
Camkii Activation

Background: Cardiac fibroblasts (CFs) are the most prevalent cell types in heart and play important roles in cardiac remodeling. While the roles of β-adrenergic receptor (βAR) signaling in cardiomyocytes (CMs) are well characterized, those in CFs remain to be elusive due to lack of convenient method to assess those signaling. There are three subtypes of, βAR β1, β2, β3 and β2AR is reported to be expressed in CFs by which enhances cell proliferation and production of inflammatory cytokines. Clinical efficacy of non-selective β blocker carvedilol for heart failure (HF) surpasses that of β1 selective blocker metoprolol, suggesting critical roles of β2 and β3AR in the pathogenesis of HF. Objective: To elucidate the signaling downstream βARs in CFs in heart. Methods and Results: Caveolae is an important microdomain for signal transduction, such as βAR, present in CMs or CFs. To elucidate βAR signaling of caveolae in CFs, we generated a fusion protein composed of phospholamban (PLN) and caveolin3 (Cav3) representing PKA activation as phosphorylation at S16 of PLN and CaMKII as that at T17 in caveolae. Thus, activation of PKA or CaMKII is detectable by anti-phospho-S16 or T17 antibody, respectively. In neonatal rat CFs (NRCFs) infected PLN-Cav3 adenovirus, stimulation by isoproterenol (ISO) led to enhanced phosphorylation of both S16 and T17, suggesting PKA and CaMKII activation in caveolae of CFs. RT-PCR analyses showed β2AR and β3AR were present in NRCFs. Stimulation with β2AR selective agonists activated both PKA and CaMKII, while β3AR elicited solely PKA activation, analyzed by using β3AR selective agonist/antagonist. In addition, in order to examine the significance of βAR stimulation for heart failure, we administered ISO continuously for two weeks in β2ARKO mice. As a result, fibrosis was suppressed in β2ARKO mice compared with wild-type mice (0.35% vs 2.37%, p<0.05) suggesting critical roles of β2AR in development of cardiac fibrosis caused by βAR stimulation in mice. Conclusions: Both β2 and β3AR are expressed in NRCFs and transduce distinct signaling and β2AR selective stimulation elicit development of cardiac fibrosis via activation of CaMKII signaling. Thus, selective βAR regulation could be potential novel anti-fibrotic therapeutics in HF.

scholarly journals Histamine deficiency induces tissue-specific down-regulation of histamine H2 receptor expression in histidine decarboxylase knockout mice

FEBS Letters ◽  
2001 ◽  
Vol 508 (2) ◽  
pp. 245-248 ◽  
Author(s):  
Carlos P. Fitzsimons ◽  
Eszter Lazar-Molnar ◽  
Zsuzsa Tomoskozi ◽  
Edit Buzás ◽  
Elena S. Rivera ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Histidine Decarboxylase ◽  
Receptor Expression ◽  
Down Regulation ◽  
Histamine H2 Receptor ◽  
Tissue Specific ◽  
H2 Receptor

A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade

2010 ◽  
Vol 105 (6) ◽  
pp. 787-794 ◽  
Author(s):  
Hiroyuki Takahama ◽  
Hiroshi Asanuma ◽  
Shoji Sanada ◽  
Masashi Fujita ◽  
Hideyuki Sasaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Receptor Blocker ◽  
Receptor Blockade ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Adrenergic Receptor Blockade

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.

Abstract 370: MicroRNA-19b Contributes to Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ping Chen ◽  
Dongchao Lv ◽  
Jiahong Xu ◽  
Qiulian Zhou ◽  
Qi Sun ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Suppressor Gene ◽  
Tissue Growth ◽  
Neonatal Rat ◽  
Cell Counting ◽  
Mrna Levels ◽  
And Migration ◽  
Proliferation And Migration

Fibrosis is one of the most important characteristics of cardiac remodeling during heart failure. The accumulation of extracellular matrix (ECM) within myocardium is the major feature of cardiac fibrosis. microRNA (miR)-19b, a key functional member of miR-19-72 cluster family, has been suggested to be involved in aging-induced heart failure through regulating ECM-related proteins, such as connective tissue growth factor (CTGF), thrombospondin-1 (TSP-1), collagen-1A1, and collagen-3A1. In the current study, we aimed to investigate the role of miR-19b in cardiac fibroblast function and ECM production using neonatal rat cardiac fibroblasts in primary culture. We found that overexpression of miR-19b increased, while inhibition of miR-19b decreased the proliferation and migration of cardiac fibroblasts, using Cell Counting Kit-8 (CCK-8) (0.660±0.019 vs 0.720±0.014 in nc-mimic and miR-19b mimic, 0.506±0.009 vs 0.454±0.008 in nc-inhibitor and miR-19b inhibitor, respectively), EdU incorporation assay (0.059±0.002 vs 0.096±0.006 in nc-mimic and miR-19b mimic, 0.059±0.006 vs 0.040±0.003 in nc-inhibitor and miR-19b inhibitor, respectively), and wound healing assay (0.528±0.024 vs 0.896±0.027 in nc-mimic and miR-19b mimic,0.520±0.028 vs 0.174±0.019 in nc-inhibitor and miR-19b inhibitor, respectively), respectively. Meanwhile, the inhibition of miR-19b downregulated the mRNA levels of α-SMA (0.556±0.048 vs 1.038±0.137 in nc-inhibitor and miR-19b inhibitor, respectively) and collagen-1 (1.023±0.116 vs 0.551±0.033 in nc-inhibitor and miR-19b inhibitor, respectively) in cardiac fibroblasts, indicating a reduction in fibroblast activation and ECM production via miR-19b inhibition. Furthermore, we found that PTEN was negatively regulated by miR-19b in cardiac fibroblasts using western blot analysis. PTEN, a well-known tumor-suppressor gene, has been known to inhibit cell proliferation and migration. However, it remains to be further clarified whether PTEN could mediate the effect of miR-19b in the proliferation, migration and activation of fibroblasts. These data might provide important evidence suggesting that miR-19b could be a potential therapeutic target for cardiac fibrosis.

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.

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