scholarly journals Dapagliflozin: a Sodium-glucose Cotransporter 2 Inhibitor, Attenuates Angiotensin II-induced Cardiac Fibrotic Remodeling by Regulating TGFβ1/ Smad Signaling

2021 ◽  
Author(s):  
Yuze Zhang ◽  
Xiaoyan Lin ◽  
Yong Chu ◽  
Xiaoming Chen ◽  
Heng Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Ang Ii ◽  
Smad Signaling ◽  
Sd Rats ◽  
Sodium Glucose Cotransporter ◽  
Tgf Β1

Abstract Background:Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms.Methods:Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II with or without the indicated concentration of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes.Results:DAPA treatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA treatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling.Conclusion:DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a glucose-independent manner. DAPA may serve as a novel therapy for pathological cardiac remodeling.

scholarly journals Dapagliflozin: a sodium–glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuze Zhang ◽  
Xiaoyan Lin ◽  
Yong Chu ◽  
Xiaoming Chen ◽  
Heng Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Ang Ii ◽  
Smad Signaling ◽  
Sd Rats ◽  
Sodium Glucose Cotransporter ◽  
Tgf Β1

Abstract Background Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. Methods Sprague–Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 μM) with or without the indicated concentration (0.5, 1, 10 μM) of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes. Results DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling. Conclusion DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.

scholarly journals Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-β1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction

2018 ◽  
Vol 45 (5) ◽  
pp. 1797-1806 ◽  
Author(s):  
Anbang Han ◽  
Yingdong Lu ◽  
Qi Zheng ◽  
Jian Zhang ◽  
YiZhou Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Rat Model ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Protective Effects ◽  
Tnf Α ◽  
Tgf Β1

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

scholarly journals HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling

2014 ◽  
Vol 307 (2) ◽  
pp. H252-H258 ◽  
Author(s):  
Kimberly M. Demos-Davies ◽  
Bradley S. Ferguson ◽  
Maria A. Cavasin ◽  
Jennifer H. Mahaffey ◽  
Sarah M. Williams ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Muscle Wasting ◽  
Striated Muscle ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Ang Ii ◽  
Skeletal Muscle Wasting

Little is known about the function of the cytoplasmic histone deacetylase HDAC6 in striated muscle. Here, we addressed the role of HDAC6 in cardiac and skeletal muscle remodeling induced by the peptide hormone angiotensin II (ANG II), which plays a central role in blood pressure control, heart failure, and associated skeletal muscle wasting. Comparable with wild-type (WT) mice, HDAC6 null mice developed cardiac hypertrophy and fibrosis in response to ANG II. However, whereas WT mice developed systolic dysfunction upon treatment with ANG II, cardiac function was maintained in HDAC6 null mice treated with ANG II for up to 8 wk. The cardioprotective effect of HDAC6 deletion was mimicked in WT mice treated with the small molecule HDAC6 inhibitor tubastatin A. HDAC6 null mice also exhibited improved left ventricular function in the setting of pressure overload mediated by transverse aortic constriction. HDAC6 inhibition appeared to preserve systolic function, in part, by enhancing cooperativity of myofibrillar force generation. Finally, we show that HDAC6 null mice are resistant to skeletal muscle wasting mediated by chronic ANG-II signaling. These findings define novel roles for HDAC6 in striated muscle and suggest potential for HDAC6-selective inhibitors for the treatment of cardiac dysfunction and muscle wasting in patients with heart failure.

scholarly journals A REVIEW ON COMPARATIVE STUDY ON THE SAFETY AND EFFECTIVENESS OF SACUBITRIL-VALSARTAN COMBINATION WITH ACE/ARB THERAPY IN CARDIAC PATIENTS

2019 ◽  
Vol 7 (2) ◽  
Author(s):  
Bhagya Suresh ◽  
Mathew George ◽  
Lincy Joseph
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Left Ventricular ◽  
At1 Receptor ◽  
Receptor Blocker ◽  
Left Ventricular Ejection ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Cv Disease

Cardiovascular (CV) disease is a major cause of morbidity and mortality in the developing and the developed world, and represents a major barrier to sustainable human development. Ischemic heart disease, cerebrovascular disease, cardiomyopathy and heart failure (HF), and hypertension among others represent major forms of CV disease. Heart failure (HF) is among the key contributors to the CV-related health care burden, a uninterrupted concern despite the utilization of clinically tried guideline-directed therapies. The most common cause for HF is reduced left cavum heart muscle perform. ARBs produce equivalent mortality benefits with fewer adverse effects than ACE inhibitors. Angiotensin converting enzyme (ACEI) reduces the combined risk of death or hospitalization, slow progression of HF, and reduced rate of reinfarction. Sacubitril/valsartan could be a first-in-class twin action molecule of the neprilysin (NEP) substance sacubitril (AHU-377) and therefore the angiotensin II (Ang II) sort one (AT1) receptor blocker (ARB) valsartan. The beneficial antihypertensive and HF effects of sacubitril/valsartan are mediated through the inhibition of NEP in catabolizing the natriuretic peptides (NPs) and the blockade of Ang II, AT1 receptor with valsartan. These actions of sacubitril/ valsartan end in general dilation and inflated symptoms and symptoms, resulting in decrease in peripheral tube resistance and plasma volume contraction, all necessary actions for the lowering of BP and improving HF symptoms. Keywords:  cardiovascular disease, left ventricular ejection fraction, angiotensin II receptor blocker, angiotensin converting enzyme, sacubitril/valsartan.

Abstract 3467: Fibulin-2 Enhances Angiotensin-II-Induced Transforming Growth Factor (TGF)-β Activation in Promoting Cardiac Remodeling in the Mouse Model I n Vivo

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hangxiang Zhang ◽  
Hailong Dong ◽  
Jing Wu ◽  
Mon-Li Chu ◽  
Takeshi Tsuda
Keyword(s):  
Angiotensin Ii ◽  
Signaling Pathways ◽  
Cardiac Remodeling ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Ang Ii ◽  
Downstream Signaling ◽  
Collagen Iii

Background: Angiotensin-II (Ang-II) is a potent neurohormone responsible for progression of cardiac remodeling in which TGF-β serves as a principal downstream mediator. In our previous study, genetic deletion of fibulin-2 attenuated progression of ventricular dysfunction after experimental myocardial infarction (MI). Because Ang-II plays a central role in post-MI ventricular remodeling, we tested the hypothesis that fibulin-2 modulates Ang-II-induced cardiac remodeling. Methods: Subpressor dosage of Ang-II (0.2 μg/kg/min) was infused over 4 weeks by mini-osmotic-pump in age matched wild-type (WT), heterozygous, and fibulin-2 null (Fbln2 −/− ) adult male mice. Sham mice received normal saline. Results: There was no blood pressure change throughout Ang-II treatment. WT developed significant left ventricular (LV) hypertrophy by Ang-II, whereas Ang-II-treated Fbln2 −/− mice showed no noticeable hypertrophy compared with sham: LV/body weight ratio (WT 4.83±0.18 vs. Fbln2 −/− 4.01± 0.12 mg/g, p < 0.05) and LV posterior wall thickness by echocardiogram (WT 0.76± 0.03 vs. Fbln2 −/− 0.71± 0.02 mm, p < 0.05). Atrial natriuretic peptide (ANP) mRNA expression was significantly increased in Ang-II-treated WT compared with sham, but not in Ang-II-treated Flbn2 −/− . Ang-II also induced significant up-regulation in fibulin-2, Collagen I, Collagen III, and MMP-2 mRNA level in WT, but not in Fbln2 −/− . Both TGF-β1 mRNA and protein expression were significantly up-regulated in Ang-II-treated WT, but were unchanged in Ang-II-treated Fbln2 −/− compared with sham. Activation of TGF-β downstream signaling proteins, phosphorylated forms of Smad2, TGF-β-activated kinase 1 (TAK1), and p38MAPK, were all significantly increased in Ang-II-treated WT, as opposed to no increase in Ang-II-treated Fbln2 −/− compared with sham. Heterozygous mice showed intermediate increase in LV hypertrophy, matrix protein synthesis, and activation of TGF-β downstream signaling pathways between WT and Fbln2 −/− . Conclusions: Our data suggest that fibulin-2 enhances Ang-II-induced myocardial hypertrophy via up-regulation of TGF-β and its downstream signaling pathways in dose-dependent fashion and that fibulin-2 is required for Ang-II-induced TGF-β activation. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

scholarly journals Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis

2021 ◽  
Vol 23 (1) ◽  
pp. 437
Author(s):  
Yang Song ◽  
Chengqun Huang ◽  
Jon Sin ◽  
Juliana de F. Germano ◽  
David J. R. Taylor ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Coronary Artery Ligation ◽  
Adverse Remodeling ◽  
Cellular Energetics

Sodium–glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.

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.

Tissue factor cytoplasmic tail regulates myeloid cell derived superoxide formation and TGF-beta 1 driven cardiac remodeling in myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V.S Garlapati ◽  
M Molitor ◽  
P Efentakis ◽  
J Lagrange ◽  
J Wild ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Tissue Factor ◽  
Cardiac Remodeling ◽  
Myeloid Cells ◽  
Cytoplasmic Tail ◽  
Left Ventricular ◽  
Superoxide Formation ◽  
Acute Mi ◽  
Tgf Β1

Abstract Background In the setting of myocardial infarction (MI), patients with coronary no-reflow and/or delayed presentation after onset of symptoms (sub-acute MI) are inflicted by severe thrombo-inflammation and are marked by worse clinical outcome. However, it is unclear whether tissue factor (TF) contributes to outcome post MI solely by the regulatory functions of its cytoplasmic tail independently of its coagulation activity. Purpose We analyzed the role of the TF cytoplasmic domain in the recruitment of myeloid cells into the infarcted myocardium and the consequences on cardiac remodeling, scar formation, development of heart failure and survival post MI. Methods Twelve Patients enrolled in the MICAT (Mainzer Intracoronary Database, ClinicalTrials.gov Identifier: NCT02180178) study were examined. Patients with sub-acute MI and stable coronary artery disease were defined and monocytes were isolated from peripheral blood mononuclear cells (PBMCs). Human heart samples acquired from the left ventricular wall of explanted hearts following cardiac transplantation or obtained during implantation of left ventricular assist device. Samples were investigated for downstream analysis of protein by western blots, RNA quantification and cryo-sectioning. MI was induced in 9 to 12 weeks old male C57BL/6J mice, mice specifically lacking the cytoplasmic tail (CT) of TF (TFΔCT mice) and TFfl/flLysMCre+/− mice by permanent ligation of the left anterior descending artery. Left ventricular function was assessed by High-Frequency Ultrasound System. Infiltration of immune cells into the infarcted myocardium was analyzed by performing flow cytometric analysis after enzymatic digestion of the myocardium. Superoxide levels were quantified by HPLC-based measurement of dihydroethidium derived oxidation product 2-hydroxy ethidium. Results Circulating monocytes in patients with sub-acute MI showed increased nitrosative stress as well as increased phosphorylation of TF CT along with TGF-β1 and NF-kB inflammatory activation, which was recapitulated in cardiac tissue of end-stage heart failure patients with chronic MI. MI results in phosphorylation of the CT of TF within myeloid cells. Using mice with conditional knockout of TF on myeloid cells or TFΔCT mice, we found that this regulatory intracellular domain of TF within myeloid cells is required for cardiac infiltration of inflammatory Ly6Chigh TF+ monocytes, Rac-1 GTPase and superoxide formation of gp91phox + myeloid cells in MI. TGF-β1 dependent SMAD2 activation and cardiac collagen deposition as late sequel of MI was reduced in TFΔCT mice, resulting in attenuated cardiac dysfunction and reduced mortality. Conclusion We conclude that, TF CT drives NADPH-oxidase derived superoxide formation, thrombo-inflammation and cardiac fibrosis. Therefore, it might serve as putative biomarker and risk predictor in MI Funding Acknowledgement Type of funding source: None

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.

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