Abstract 16383: Inhibition of Egfr Signalling Promotes Maladaptive Cardiac Remodelling in Hypertensive Heart Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Susanna Cooper ◽  
Zoe Haines ◽  
Viridiana Alcantara Alonso ◽  
Joshua J Cull ◽  
Feroz Ahmad ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mrna Expression ◽  
Left Ventricular ◽  
Egfr Inhibitors ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Egfr Ligands ◽  
Cardiac Adaptation

Introduction: Epidermal growth factor (EGF) receptors (EGFRs: ERBB1-4) are activated by a family of ligands (e.g. EGF, Hb-EGF, EREG, TGFa), signaling through ERK1/2 and Akt to promote cell division and cancer. Antibody-based inhibition of ERBB2 in breast cancer can cause heart failure, but the role of other receptors and EGFR ligands in the heart, and potential cardiotoxicity of generic EGFR inhibitors is unclear. Hypothesis: We hypothesize that EGFR ligands play an important role in cardiac adaptation to hypertension, acting through EGFRs to promote adaptive remodelling. Methods & Results: EGF ligand/receptor mRNA expression was assessed in human failing hearts and normal controls (n=12/8). EGFRs were expressed at similar levels, but ligand expression differed with significant up- or downregulation of EGF/Hb-EGF vs EREG/TGFa, respectively, in failing hearts (p<0.05). EGF potently activated ERK1/2 and Akt (assessed by immunoblotting) in neonatal rat cardiomyocytes, leading to hypertrophy (p<0.05, n=4). The anti-cancer drug afatinib inhibits EGFRs. To assess the role of EGF signaling in cardiac adaptation to hypertension in vivo , C57Bl/6J mice (n=6) were treated with 0.8 mg/kg/d angiotensin II (AngII; 7d) ± 0.45 mg/kg/d afatinib. AngII promoted cardiac hypertrophy with increased left ventricular (LV) wall thickness (WT) and decreased LV internal diameter (ID; assessed by echocardiography). Afatinib enhanced AngII-induced hypertrophy with significantly increased WT:ID ratios (1.30-fold and 1.54-fold in diastole and systole, respectively; p<0.05) but inhibited AngII-induced increases in Nppb mRNA expression and cardiomyocyte cross-sectional area (208.80±9.78 vs 161.10±3.87μm 2 ; p<0.05). In contrast, Col1a1 mRNA expression was enhanced by afatinib, along with interstitial and perivascular fibrosis (3.21±0.38 vs 5.61±0.46, 0.98±0.06 vs 1.45±0.18 % area; p<0.05). Conclusion: EGFR signaling is modulated in human heart failure, promotes cardiomyocyte hypertrophy and is required for cardiac adaptation to hypertension. Since EGFR inhibition in hypertension prevents adaptive cardiomyocyte hypertrophy whilst promoting fibrosis, EGFR inhibitors are likely to cause cardiac dysfunction and be cardiotoxic in hypertensive patients.

Abstract 320: Roles of Estrogen, AMPK and Micro RNAs in the Progression of Cardiac Hypertrophy

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Yulia Lipovka ◽  
John P Konhilas
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Estradiol Treatment ◽  
Rat Cardiomyocytes ◽  
Altered Expression ◽  
Ampk Pathway ◽  
Micro Rnas

In industrialized countries, the prevalence of congestive heart failure (CHF) is increasing steadily and has become one of the leading causes of hospitalization. In addition, the risk of cardiovascular disease increases in post-menopausal women. Yet, the association between estrogen and the risk of CHF has not been adequately studied. Recently, MicroRNAs (miR) and AMP-kinase (AMPK) have emerged as prominent players in the development of cardiac hypertrophy and heart failure. Our on-going studies indicate differential AMPK regulation through two miR species (miR195 and miR451) in a mouse model harboring a missense mutation (R403Q) in alpha-myosin heavy chain (αMHC) causing hypertrophic cardiomyopathy (HCM). Using bioinformatic algorithms (TargetScanMouse, 5.2), we were able to predict miR candidates that potentially target the AMPK axis. In addition, Altered expression of miRs that target AMPK axis was found in phenylephrine induced hypertrophic neonatal rat cardiomyocytes (NRCM). However, Estradiol treatment of NRCM blocked the hypertrophic changes induced by phenylephrine treatment. It was known that the activation of AMPK pathway inhibits cardiomyocyte hypertrophy. Our data showed that AMPK pathway was activated by Estradiol treatment, which can be blocked by estrogen receptor (ER) β antagonist. Therefore, estradiol increase AMPK pathway activation which in turn attenuate phenylephrine induced increase in cardiomyocyte cell size. Further studies are need to further explore the role of estrogen in the regulation of miR expression in hypertrophic cardiomyocytes, and the role of the expression changes of miRs regulated by estrogen in the development of hypertrophic phenotype.

scholarly journals Sophoricoside ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Maomao Gao ◽  
Fengjiao Hu ◽  
Manli Hu ◽  
Yufeng Hu ◽  
Hongjie Shi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy ◽  
Compound C

Abstract Aim: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, the potential and significance of Sop should be broadened and it should be considered as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure. Methods: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) enlargement model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At 1 week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination. Results: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulation. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy. Conclusion: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.

mTOR signaling-related microRNAs as cardiac hypertrophy modulators in high‐volume endurance training

2021 ◽  
Author(s):  
Bruno R.A. Pelozin ◽  
Ursula Paula Reno Soci ◽  
João L. P. Gomes ◽  
Edilamar Menezes Oliveira ◽  
Tiago Fernandes
Keyword(s):  
Protein Expression ◽  
Molecular Mechanisms ◽  
High Volume ◽  
Left Ventricular ◽  
Mtor Signaling ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Peak Exercise ◽  
Dependent Manner ◽  
Rat Cardiomyocytes

Aerobic exercise training (ET) promotes cardiovascular adaptations, including physiological left ventricular hypertrophy (LVH). However, the molecular mechanisms that underlying these changes are unclear. The study aimed to elucidate specific miRNAs and target genes involved with the Akt/mTOR signaling in high-volume ET-induced LVH. Eight-week-old female Wistar rats were assigned to three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 minutes/day of swimming, 5x/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week; in the 9th week, rats trained 2x/day, and in the 10th week, trained 3x/day. Subsequently, structure and molecular parameters were evaluated in the heart. Trained groups demonstrate higher values to VO2 peak, exercise tolerance, and LVH in a volume-dependent manner. The miRNA-26a-5p levels were higher in P1 and P2 compared to SC group (150±15%, d=1.8; 148±16%, d=1.7; and 100±7%, respectively, P < 0.05). In contrast, miRNA-16-5p levels were lower in P1 and P2 compared to SC group (69±5%, d=2.3, P < 0.01; 37±4%, d=5.6, P < 0.001 and 100±6%, respectively). Additionally, miRNA-16-5p knockdown and miRNA-26a-5p overexpression significantly promoted cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. Both miRNAs were selected, using Diana Tolls bioinformatics website, for acting in the mTOR signaling pathway. The protein expression of Akt, mTOR, p70S6k, and 4E-BP1 were greater in P1 and even more pronounced in P2. Nonetheless, GSK3β protein expression was lower in trained groups. Together, these molecular changes may contribute to a pronounced physiological LVH observed in high-volume aerobic training.

scholarly journals Thyroid Hormone-Induced Cardiac Mechano Growth Factor Expression Depends on Beating Activity

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 830-838 ◽  
Author(s):  
Miriam van Dijk-Ottens ◽  
Ingrid H. C. Vos ◽  
Peter W. A. Cornelissen ◽  
Alain de Bruin ◽  
Maria E. Everts
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Mrna Expression ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Mechano Growth Factor ◽  
Physiological Cardiac Hypertrophy

The mechano growth factor (MGF), a splice variant of the IGF-I gene, was first discovered in mechanically overloaded skeletal muscle and was shown to play an important role in proliferation of muscle stem cells. Since then, the presence and effects of MGF have been demonstrated in other tissues. MGF has been shown to act neuroprotectively during brain ischemia, and pretreatment with MGF before myocardial infarction improves cardiac function. Because MGF plays a permissive role in exercise-induced skeletal muscle hypertrophy, we hypothesize that MGF is commonly involved in cardiac hypertrophy. To investigate the regulation of MGF expression in heart, mice were treated with thyroid hormone (T3) for 12 d to induce physiological cardiac hypertrophy. MGF mRNA expression was specifically increased in midregions of the septum and left ventricular wall. Interestingly, MGF expression strongly correlated with the increased or decreased beating frequency of hyperthyroid and hypothyroid hearts. To further investigate the mechanically dependent induction of MGF, neonatal rat cardiomyocytes were isolated and exposed to T3. Upon T3 treatment, cardiomyocytes increased both contractile activity measured as beats per minute and MGF as well as IGF-IEa mRNA expression. Importantly, when cardiomyocytes were contractile arrested by KCl, simultaneous exposure to T3 prevented the up-regulation of MGF, whereas IGF-IEa was still induced. These studies demonstrated that MGF but not IGF-IEa expression is dependent on beating activity. These findings suggest that MGF is specifically stimulated by mechanical loading of the heart to mediate the hypertrophic response to thyroid hormone.

scholarly journals Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction

2021 ◽  
Vol 12 ◽  
Author(s):  
Liyun Zhang ◽  
Juan Chen ◽  
Lianhua Yan ◽  
Qin He ◽  
Han Xie ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Mrna Expression ◽  
Cardiac Remodeling ◽  
Transcriptional Activity ◽  
Left Ventricular ◽  
Sirtuin 1 ◽  
Neonatal Rat ◽  
Preserved Ejection Fraction ◽  
Underlying Mechanisms

Objective: Accumulating evidence suggested that resveratrol (RES) could protect against adverse cardiac remodeling induced by several cardiovascular diseases. However, the role of RES in the setting of heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain understood. This study was to determine whether RES could ameliorate HFpEF-induced cardiac remodeling and its mechanisms.Methods:In vivo, C57BL/6 mice served as either the sham or the HFpEF model. The HFpEF mice model was induced by uninephrectomy surgery and d-aldosterone infusion. RES (10 mg/kg/day, ig) or saline was administered to the mice for four weeks. In vitro, transforming growth factor β1 (TGF-β1) was used to stimulate neonatal rat cardiac fibroblasts (CFs) and Ex-527 was used to inhibit sirtuin 1 (Sirt1) in CFs. Echocardiography, hemodynamics, western blotting, quantitative real-time PCR, histological analysis, immunofluorescence, and ELISA kits were used to evaluate cardiac remodeling induced by HFpEF. Sirt1 and Smad3 expressions were measured to explore the underlying mechanisms of RES.Results: HFpEF mice developed left ventricular hypertrophy, preserved ejection fraction, diastolic dysfunction, and pulmonary congestion. Moreover, HFpEF mice showed increased infiltration of neutrophils and macrophages into the heart, including increased interleukin (IL)-1β, IL-6, and TNF-α. We also observed elevated M1 macrophages and decreased M2 macrophages, which were exhibited by increased mRNA expression of M1 markers (iNOS, CD86, and CD80) and decreased mRNA expression of M2 markers (Arg1, CD163, and CD206) in HFpEF hearts. Moreover, HFpEF hearts showed increased levels of intracellular reactive oxygen species (ROS). Importantly, HFpEF mice depicted increased collagen-I and -III and TGF-β mRNA expressions and decreased protein expression of phosphorylated endothelial nitric-oxide synthase (p-eNOS). Results of western blot revealed that the activated TGF-β/Smad3 signaling pathway mediated HFpEF-induced cardiac remodeling. As expected, this HFpEF-induced cardiac remodeling was reversed when treated with RES. RES significantly decreased Smad3 acetylation and inhibited Smad3 transcriptional activity induced by HFpEF via activating Sirt1. Inhibited Sirt1 with Ex-527 increased Smad3 acetylation, enhanced Smad3 transcriptional activity, and offset the protective effect of RES on TGF-β–induced cardiac fibroblast–myofibroblast transformation in CFs.Conclusion: Our results suggested that RES exerts a protective action against HFpEF-induced adverse cardiac remodeling by decreasing Smad3 acetylation and transcriptional activity via activating Sirt1. RES is expected to be a novel therapy option for HFpEF patients.

Abstract 172: Interleukin-10-mediated Activation of AKT and Bcl2 Inhibits Chronic Angiotensin II-induced Pathological Autophagy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Suresh K Verma ◽  
Prasanna Krishnamurthy ◽  
Venkata N Girikipathi ◽  
Tatiana Abramova ◽  
Moshin Khan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Pressure Overload ◽  
Interleukin 10 ◽  
Left Ventricular ◽  
Beclin 1 ◽  
Neonatal Rat ◽  
Physical Interaction ◽  
Ang Ii

Rationale: Although, autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological (stress-induced exaggerated/defective) autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is not known. Hypothesis: We tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, led to improved cardiac function. Methods and Results: Pathological autophagy was induced in wild type (WT) and IL10-knockout (IL-10 KO) mice by angiotensin II (Ang II for 28 days) infusion. Ang II-induced left ventricular (LV) dysfunction and hypertrophic remodeling were accentuated in IL-10 KO mice compared to WT mice. IL-10 KO mice showed exaggerated autophagy as observed by Electron Microscopy and Western blotting (beclin 1, LC3 II/I and CHOP) with reduced AKT phosphorylation at serine-473. In neonatal rat ventricular cardiomyocytes (NRCM), Ang II treatment enhanced beclin1, LC3 and CHOP protein levels and inhibited AKT and 4EBP1 phosphorylation and Bcl2 levels. Interestingly, IL-10 inhibited Ang II-induced autophagic marker proteins. Additionally, IL-10 restored Ang II-induced suppression of AKT and 4EBP1 phosphrylation and restoration of Bcl2 protein level. Pharmacological inhibition of AKT via PI3K inhibitor (LY290002), reversed IL-10 responses on the Ang II-induced pathological autophagy, confirming that IL-10 mediated inhibition of autophagy is AKT dependent. Finally, as physical interaction of Bcl2 with beclin 1 is important to inhibit autophagy, we performed immunoprecipitation pull-down experiments, which showed Ang II disrupts the physical interaction of beclin 1 with Bcl2 and IL-10 reestablished this physical interaction to reduce autophagy. Conclusion: Our data provides a novel role of IL-10 in regulation of pathological autophagy and thus can act as a potential therapeutic molecule in treatment of chronic heart disease.

Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level

2008 ◽  
Vol 294 (6) ◽  
pp. E1119-E1126 ◽  
Author(s):  
Biao Feng ◽  
Shali Chen ◽  
Jane Chiu ◽  
Biju George ◽  
Subrata Chakrabarti
Keyword(s):  
Mrna Expression ◽  
Binding Protein ◽  
Diabetic Rats ◽  
Epigenetic Mechanism ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Transcriptional Level ◽  
Transcriptional Coactivator ◽  
Rat Cardiomyocytes ◽  
Coactivator P300

Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leads to heart failure. We investigated the role of transcriptional coactivator p300 and its interaction with myocyte enhancer factor 2 (MEF2) in diabetes-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed to variable levels of glucose. Cardiomyocytes were analyzed with respect to their size. mRNA expression of p300, MEF2A, MEF2C, atrial natriuretic polypeptide (ANP), brain natriuretic polypeptide (BNP), angiotensinogen (ANG), cAMP-responsive element binding protein-binding protein (CBP), and protein analysis of MEF2 were done with or without p300 blockade. We investigated the hearts of STZ-induced diabetic rats and compared them with age- and sex-matched controls after 1 and 4 mo of followup with or without treatment with p300 blocker curcumin. The results were that cardiomyocytes, exposed to 25 mM glucose for 48 h, showed cellular hypertrophy and augmented mRNA expression of ANP, BNP, and ANG, molecular markers of cardiac hypertrophy. Glucose caused a duration-dependent increase of mRNA and protein expression in MEF2A and MEF2C and transcriptional coactivator p300. Curcumin, a p300 blocker, and p300 siRNA prevented these abnormalities. Similarly, ANP, BNP, and ANG mRNA expression was significantly higher in the hearts of diabetic rats compared with the controls, in association with increased p300, MEF2A, and MEF2C expression. Treatment with p300 blocker curcumin prevented diabetes-induced upregulation of these transcripts. We concluded that data from these studies demonstrate a novel glucose-induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes.

scholarly journals miR-139-5p inhibits isoproterenol-induced cardiac hypertrophy by targetting c-Jun

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Su Ming ◽  
Wang Shui-yun ◽  
Qiu Wei ◽  
Li Jian-hui ◽  
Hui Ru-tai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Monogenic Disease ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes ◽  
Regulatory Effects

Hypertrophic cardiomyopathy (HCM) is a serious monogenic disease characterized by cardiac hypertrophy, fibrosis, sudden cardiac death, and heart failure. Previously, we identified that miR-139-5p was down-regulated in HCM patients. However, the regulatory effects of miR-139-5p remain unclear. Thus, we investigated the role of miR-139-5p in the regulation of cardiac hypertrophy. The expression of miR-139-5p in left ventricular tissues in HCM patients and mice subjected to transverse aortic constriction (TAC) was significantly down-regulated. Knockdown of miR-139-5p expression in neonatal rat cardiomyocytes (NRCMs) induced cardiomyocyte enlargement and increased atrial natriuretic polypeptide (ANP) expression. Overexpression of miR-139-5p antagonized isoproterenol (ISO)-induced cardiomyocyte enlargement and ANP/brain natriuretic peptide (BNP) up-regulation. More importantly, we found that c-Jun expression was inhibited by miR-139-5p in NRCMs. Knockdown of c-Jun expression significantly attenuated cardiac hypertrophy induced by miR-139-5p deprivation. Our data indicated that miR-139-5p was down-regulated in the hearts of HCM patients and that it inhibited cardiac hypertrophy by targetting c-Jun expression.

scholarly journals LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shi Peng ◽  
Xiao-feng Lu ◽  
Yi-ding Qi ◽  
Jing Li ◽  
Juan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

Abstract 301: Cavin-2 Deletion Attenuates Fibroblast Activation and Cardiac Fibrosis via TGF-β Signaling by Interacting With Hsp90

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yusuke Higuchi ◽  
Takehiro Ogata ◽  
Naohiko Nakanishi ◽  
Akira Sakamoto ◽  
Yumika Tsuji ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mrna Expression ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
High Morbidity ◽  
Type I ◽  
Smad Signaling ◽  
Fibroblast Activation ◽  
Tgf Β1

Introduction: Heart failure (HF) is a progressive disease associated with high morbidity and mortality. A major cause of HF is the adverse tissue remodeling with interstitial fibrosis. Excessive extracellular matrix (ECM) accumulation is involved in the poor outcome. Transformation to myofibroblasts in resident fibroblasts has an important role for cardiac fibrosis on pressure-overload heart failure. TGF-β signaling is one of the critical pathways in fibroblast activation. Caveolae are major plasma membrane domain defined as 50-100 nm vesicular structures. Caveolins and cavins are known as caveolar-related proteins. TGF-β signaling is tightly connected with caveolae. A previous report shows that induction of Cav-1 expression leads to suppression of TGF-β signaling and an improvement of fibrosis. Although cavin-2/Serum deprivation response protein (SDPR) is also abundant in fibroblasts, the role of cavin-2 in cardiac fibrosis and function remains unknown. Methods and Results: To clarify the role of cavin-2 in cardiac fibroblasts in the pressure-overloaded heart, we performed TAC operation on cavin-2 flox/flox mice and fibroblast-specific cavin-2 knockout (Postin Cre ; SDPR flox/flox ) mice (cavin-2 cKO). Four weeks after TAC, left ventricular fractional shortening (LVFS) was preserved with a significant reduction of cardiac fibrosis in cavin-2 cKO mice. Fibrosis-associated mRNA expression ( Col1a1, Ctgf, Col3 ) and α1 type I collagen deposition were reduced in the hearts of cavin-2-cKO mice after TAC. Transdifferentiation of fibroblasts into activated myofibroblasts is a defining feature of fibrosis. Myofibroblasts express αSMA and secrete ECM proteins via Smad signaling. αSMA-positive cells without showing vascular structure were reduced in cavin-2 cKO after TAC. In mouse embryonic fibroblasts (MEFs), cavin-2 deficiency reduced TGF-β1-induced αSMA production and fibrosis-associated mRNA expression. On the other hand, adenovirus-mediated cavin-2 overexpression significantly increased αSMA production and the fibrosis-associated mRNA expressions. Furthermore, TGF-β1-induced Smad2/3 phosphorylation was attenuated in cavin-2 KO MEFs compared to wild-type (WT) MEFs. A protein-Protein interaction screening using a promiscuous biotin ligase, called BioID, revealed that cavin-2 interacted with Hsp90ab1 and Hsp90b1 which modulate collagen synthesis through regulation of SMA and SMAD pathway. The protein expression level of Hsp90 in cavin-2 KO MEFs significantly decreased compared with that in WT MEFs. Conclusions: Our observations suggest that cavin-2 contributes to the development of cardiac fibrosis through the differentiation from fibroblasts into myofibroblasts via TGF-β/Smad signaling. cavin-2 may be a novel therapeutic target for cardiac fibrosis.

Sign in / Sign up

Export Citation Format

Share Document