scholarly journals 2-Arachidonoylglycerol Attenuates Fibrosis in Diabetic Mice via the TGF-β1/Smad Pathway

2021 ◽  
Author(s):  
Zhengjie Chen ◽  
Liangyu Zheng ◽  
Gang Chen
Keyword(s):  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Myocardial Cell ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Tgf Β1

Abstract Purpose: Diabetic cardiomyopathy (DM) is the cause of late cardiac dysfunction in diabetic patients. Myocardial fibrosis is the main pathological mechanism, which is associated with transforming growth factor-β1(TGF-β1) expression up-regulation. 2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid that can effectively improve myocardial cell energy metabolism and cardiac function. Here, we evaluated the protective effect of 2-AG on diabetic cardiomyopathy.Methods: Male C57BL/6J mice were injected with 2-AG intraperitoneally for 4 weeks (1μg/kg/day) after 12 weeks of diabetic modeling. After 4 weeks, heart function was evaluated by echocardiography. Heart structure was assessed by hematoxylin and eosin staining. Cardiac fibrosis was analyzed using immunohistochemistry, Sirius red stain and Western blot.Results: After modeling in diabetic mice, cardiac ultrasonography showed decreased cardiac function, and pathological findings showed that myocardial fibrosis. 2-AG could effectively inhibit the up-regulation of TGF-β1 and Smad2/3, improve myocardial fibrosis and ultimately improve cardiac function in diabetic mice.Conclusion: 2-AG reduces cardiac fibrosis via the TGF-β1/Smad2/3 pathway and is a potential pathway for the treatment of cardiac dysfunction in diabetic mice.

scholarly journals Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction

2016 ◽  
Vol 38 (5) ◽  
pp. 1928-1938 ◽  
Author(s):  
Mian Cheng ◽  
Gang Wu ◽  
Yue Song ◽  
Lin Wang ◽  
Ling Tu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Signalling Pathway ◽  
Tgf Β1

Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms. Methods: Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC) in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming growth factor beta 1 (TGF-β1), extracellular signal regulated kinases 1/2 (ERK1/2) signalling were measured using Western blotting, while the expression of miR-21was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac fibroblasts (CFs) were treated with TGF-β1 and transfected with microRNA-21(miR21). Results: Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA), atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP), beta-myosin heavy chain (β-MHC), miR-21 and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-21/ERK signalling pathway. Celastrol attenuated miR-21 up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-21. Conclusion: MiR-21/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-21/ERK signaling pathways in vitro and in vivo.

Hypertriglyceridemia in experimental diabetes: relationship to cardiac dysfunction

1994 ◽  
Vol 72 (5) ◽  
pp. 447-455 ◽  
Author(s):  
Brian Rodrigues ◽  
Paul F. Grassby ◽  
Mary L. Battell ◽  
Stephanie Y. N. Lee ◽  
John H. McNeill
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Plasma Triglyceride ◽  
Diabetic Rat ◽  
Diabetic Patients ◽  
Beneficial Effects ◽  
Rate Of Increase

The incidence of mortality from cardiovascular disease is higher in diabetic patients. The objective of the present investigation was to test die hypothesis that the diabetes-induced depression in cardiac function may be due to hypertriglyceridemia. Hyperlipidemia and a depressed left ventricular developed pressure and rate of increase and decrease of ventricular pressure (±dP/dt) were produced in isolated hearts from rats made diabetic with streptozotocin compared with hearts from control animals. This depressed cardiac performance was successfully prevented by hydralazine treatment (for 3 weeks), which also lowered plasma triglyceride levels and suggested that hyperlipidemia may be important in altering cardiac function in experimental diabetic rats. The beneficial effects of clofibrate, verapamil, prazosin, enalapril, and benazepril administration were then studied in diabetic rats. The treatments (with die exception of enalapril) significantly reduced plasma triglyceride levels but did not prevent die onset of heart dysfunction in chronically diabetic rats. These studies suggest that in the chronically diabetic rat, hypertriglyceridemia may not be as important as previously suggested, in the development of cardiac dysfunction. Since acute dichloroacetate perfusion improves cardiac function in 6 week (but not 24 week) diabetic rats, it appears more likely that improving myocardial glycose utilization is more critical than triglyceride lowering, in preventing cardiac dysfunction in die diabetic rat at this time point.Key words: diabetes, triglycerides, heart function, glucose oxidation.

scholarly journals Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel

2021 ◽  
Vol 9 ◽  
Author(s):  
Tian Jia ◽  
Xiaozhi Wang ◽  
Yiqun Tang ◽  
Wenying Yu ◽  
Chenhui Li ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Receptor Potential ◽  
Transforming Growth Factor Β ◽  
Permeable Channel ◽  
Transient Receptor ◽  
Tgf Β1

Heart failure caused by cardiac fibrosis has become a major challenge of public health worldwide. Cardiomyocyte programmed cell death (PCD) and activation of fibroblasts are crucial pathological features, both of which are associated with aberrant Ca2+ influx. Transient receptor potential cation channel subfamily M member 7 (TRPM7), the major Ca2+ permeable channel, plays a regulatory role in cardiac fibrosis. In this study, we sought to explore the mechanistic details for sacubitril, a component of sacubitril/valsartan, in treating cardiac fibrosis. We demonstrated that sacubitril/valsartan could effectively ameliorate cardiac dysfunction and reduce cardiac fibrosis induced by isoprotereno (ISO) in vivo. We further investigated the anti-fibrotic effect of sacubitril in fibroblasts. LBQ657, the metabolite of sacubitril, could significantly attenuate transforming growth factor-β 1 (TGF-β1) induced cardiac fibrosis by blocking TRPM7 channel, rather than suppressing its protein expression. In addition, LBQ657 reduced hypoxia-induced cardiomyocyte PCD via suppression of Ca2+ influx regulated by TRPM7. These findings suggested that sacubitril ameliorated cardiac fibrosis by acting on both fibroblasts and cardiomyocytes through inhibiting TRPM7 channel.

scholarly journals Salvia miltiorrhizaandCarthamus tinctoriusExtract Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction by Epigenetically Inhibiting Smad3 Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jing Yang ◽  
Bo Wang ◽  
Na Li ◽  
Qingqing Zhou ◽  
Wenhui Zhou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Histone Methylation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Salvia Miltiorrhiza ◽  
Left Ventricular

The incidence of cardiac dysfunction after myocardial infarction (MI) continues to increase despite advances in treatment. Excessive myocardial fibrosis plays a vital role in the development of adverse cardiac remodeling and deterioration of cardiac function. Understanding the molecular and cellular mechanism of the fibrosis process and developing effective therapeutics are of great importance.Salvia miltiorrhizaandCarthamus tinctoriusextract (SCE) is indicated for angina pectoris and other ischemic cardiovascular diseases in China. SCE has been shown to inhibit the platelet activation and aggregation, ameliorate ROS-induced myocardial necrosis by inhibiting mitochondrial permeability transition pore opening, and promote angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). However, whether SCE has effect on cardiac fibrosis after MI is not fully clear. Here, a mouse model of MI was established to observe the effect of SCE upon survival, cardiac function, myocardial fibrosis, and inflammation. Quantitative PCR and western blot assays were used to determine the expression of genes related to transforming growth factor-β(TGF-β) cascade and inflammatory responsesin vivo. Additionally, the effects of SCE upon the collagen production, TGF-β/Smad3 (SMAD family member 3) signaling, and the levels of histone methylation in primary cardiac fibroblasts were detected. We found that SCE treatment significantly improved survival and left ventricular function in mice after MI. Inhibition of inflammation and fibrosis, as well as decreased expression of Smad3, was observed with SCE treatment. In TGF-β-stimulated cardiac fibroblasts, SCE significantly decreased the expression of collagen,α-smooth muscle actin (α-SMA), and Smad3. Furthermore, SCE treatment downregulated the levels of H3K4 trimethylation (H3K4me3) and H3K36 trimethylation (H3K36me3) at theSmad3promoter region of cardiac fibroblasts, leading to inhibition ofSmad3transcription. Our findings suggested that SCE prevents myocardial fibrosis and adverse remodeling after MI with a novel mechanism of suppressing histone methylation of theSmad3promoter and its transcription.

scholarly journals Characterization of ferroptosis in kidney tubular cell death under diabetic conditions

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Seonghun Kim ◽  
Shin-Wook Kang ◽  
Jeongho Joo ◽  
Seung Hyeok Han ◽  
Huiyoon Shin ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Lipid Peroxide ◽  
Tubular Cell ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Glutathione Concentration ◽  
Tgf Β1

AbstractKidney tubular cell death induced by transforming growth factor-β1 (TGF-β1) is known to contribute to diabetic nephropathy, a major complication of diabetes. Caspase-3-dependent apoptosis and caspase-1-dependent pyroptosis are also involved in tubular cell death under diabetic conditions. Recently, ferroptosis, an atypical form of iron-dependent cell death, was reported to cause kidney disease, including acute kidney injury. Ferroptosis is primed by lipid peroxide accumulation through the cystine/glutamate antiporter system Xc− (xCT) and glutathione peroxidase 4 (GPX4)-dependent mechanisms. The aim of this study was to evaluate the role of ferroptosis in diabetes-induced tubular injury. TGF-β1-stimulated proximal tubular epithelial cells and diabetic mice models were used for in vitro and in vivo experiments, respectively. xCT and GPX4 expression, cell viability, glutathione concentration, and lipid peroxidation were quantified to indicate ferroptosis. The effect of ferroptosis inhibition was also assessed. In kidney biopsy samples from diabetic patients, xCT and GPX4 mRNA expression was decreased compared to nondiabetic samples. In TGF-β1-stimulated tubular cells, intracellular glutathione concentration was reduced and lipid peroxidation was enhanced, both of which are related to ferroptosis-related cell death. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, alleviated TGF-β1-induced ferroptosis. In diabetic mice, kidney mRNA and protein expressions of xCT and GPX4 were reduced compared to control. Kidney glutathione concentration was decreased, while lipid peroxidation was increased in these mice, and these changes were alleviated by Fer-1 treatment. Ferroptosis is involved in kidney tubular cell death under diabetic conditions. Ferroptosis inhibition could be a therapeutic option for diabetic nephropathy.

scholarly journals KLF15 Negatively Regulates Cardiac Fibrosis and SDF-1β Attenuates Cardiac Fibrosis Through KLF15 Pathway in Type 2 Diabetic Mice

2020 ◽  
Author(s):  
Yuanyuan Tian ◽  
Zhenyu Wang ◽  
Xiangyu Zheng ◽  
Shihuan Cheng ◽  
Wenjing Song ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Fasting Blood Glucose ◽  
Conditional Knockout ◽  
Diabetic Patients ◽  
H9c2 Cells ◽  
Diabetic Mice ◽  
Wild Type

Abstract Background: Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. Cardiac fibrosis is the major pathologic changes, for which the effective and safe approaches remain not available. Methods: Wild-type mice and conditional knockout of cardiac specific Klf15 gene (Klf15-cKO) mice were fed with either high fat diet (HFD, 60% kcal from fat) or normal diet (ND, 10% kcal from fat) for 3 months and then injected with streptozotocin or vehicle. Five days later mice with hyperglycemia (3 h fasting blood glucose level ≥ 250 mg/dL) were defined as type 2 diabetes (T2D). All T2D and age-matched control mice that were continually received their HFD or ND for 6 months were treated with or without SDF-1β at 5 mg/kg body-weight twice a week for 3 months. At the end of 9-month study, after cardiac functions measured, mice were euthanized, for collecting heart tissue. For the in vitro study, H9C2 cells were exposed to palmitate to mimic in vivo condition of T2D.Results: SDF-1β treatment attenuated T2D-induced cardiac dysfunction and fibrosis and down-regulated KLF15 expression in wild type diabetic mice. The inhibitory effect of SDF-1β on cardiac fibrosis was abolished in Klf15-cKO/T2D mice, demonstrating the KLF15-dependence for this protection. Pre-treatment of H9C2 cells with the relevant siRNAs, followed by treatment with palmitate or SDF-1b or palmitate/SDF-1b demonstrated that SDF-1β inhibited palmitate-induced myocardial fibrosis through its receptor CXCR7 mediated activation of p38β MAPK and subsequent blockade of KLF15 down-regulation. Conclusions: T2D-promoted cardiac fibrosis and dysfunction were prevented with SDF-1β treatment by up-regulating KLF15 expression. Conditional knockout of cardiac specific Klf15 gene abolishes SDF-1β prevention of cardiac fibrosis but not cardiac dysfunction. The SDF-1β’s anti-fibrosis effect in the heart of T2D is probably mediated through CXCR7-mediated p38β MAPK activation of KLF15 function.

scholarly journals Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1–Endothelin-1 Signal Pathway

Circulation ◽  
2019 ◽  
Vol 140 (8) ◽  
pp. 665-680 ◽  
Author(s):  
Jie Liu ◽  
Tao Zhuang ◽  
Jingjiang Pi ◽  
Xiaoli Chen ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Target Delivery ◽  
Endothelin 1 ◽  
Forkhead Box ◽  
Tgf Β1

Background: Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms. Methods: Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Results: Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II–induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1–promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion–mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1–siRNA to ECs. Conclusions: EC-Foxp1 regulates the TGF-β1–endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC–Foxp1–TGF-β1–endothelin-1 pathway might provide a future novel therapy for heart failure.

Abstract 269: Miofibroblast Tgf-beta Signaling in a Proteotoxic Mouse Model

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Bidur Bhandary ◽  
Qinghang Meng ◽  
Hanna Osinska ◽  
Kritton Shay-Winkler ◽  
James Gulick ◽  
...  
Keyword(s):  
Heart Disease ◽  
Mouse Model ◽  
Cardiac Function ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Prolonged Survival ◽  
Tgfβ Signaling ◽  
Specific Expression ◽  
Western Blots

Introduction: Transforming Growth Factor Beta (TGFβ) is an important cytokine in mediating the fibrogenic response and, in particular, cardiac fibrosis. Extensive fibrosis accompanies the cardiac remodeling that occurs during development of the protein conformation-based disease caused by cardiomyocyte-specific expression of a mutant, small, heat shock-like protein and chaperone, aB crystallin (CryABR120G). During the onset of fibrosis, fibroblasts are activated to the so-called “myofibroblast” state and TGFβ binding is thought to mediate an essential signaling pathway underlying this process. Our central hypothesis is that TGFβ signaling processes that result in significant cardiac fibrosis in a mouse model of proteotoxic heart disease are mediated by cardiac fibroblasts, rather than cardiomyocytes. Here, we have partially ablated TGFβ signaling only in cardiac myofibroblasts to observe if cardiac fibrosis is reduced. Aims and Methods: The objective of this study was to understand the contributions of fibroblast-derived TGFβ signaling to the development of cardiac fibrosis in a proteotoxic mouse model that results in significant cardiac fibrosis. To test the hypothesis we partially deleted the myofibroblast specific canonical and non-canonical signaling by crossing CryAB R120G mice with Tgfbr1 or Tgfbr2 floxed mice. The double transgene containing mice were further crossed with activated myofibroblast specific Cre mice in which Cre expression was driven off the periostin promoter. Echocardiography, Masson’s Trichome staining, PCR arrays, IHC and western blots were performed to characterize the fibrotic progression in CryAB R120G transgenic mice. Results: We observed that myofibroblast-targeted partial knockdown of Tgf βr1 signaling prolonged survival, modestly reducing fibrosis and improving cardiac function . Similarly, Tgf βr2 partial knockdown prolonged survival, modestly reducing fibrosis without improving cardiac function during fibrosis development in CryAB R120G mice. Conclusion: These findings suggest that, in a model of proteotoxic heart disease, myofibroblast based TGFβ signaling in the heart may contribute to cardiac hypertrophy/dysfunction but cannot account entirely for the fibrotic response.

Transforming growth factor-β3 (TGF-β3) loaded PLGA-b-PEG nanoparticles: Efficacy in preventing cardiac fibrosis induced by TGF-β1

2018 ◽  
Vol 48 ◽  
pp. 223-234 ◽  
Author(s):  
Samiye Yabanoglu-Ciftci ◽  
Ipek Baysal ◽  
Acelya Erikci ◽  
Betul Arıca ◽  
Gulberk Ucar
Keyword(s):  
Growth Factor ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Tgf Β1

scholarly journals Effect of miR-195-5p on cardiomyocyte apoptosis in rats with heart failure by regulating TGF-β1/Smad3 signaling pathway

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Chun Xie ◽  
Huaxin Qi ◽  
Lei Huan ◽  
Yan Yang
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Reporter ◽  
Rat Cardiomyocytes ◽  
Smad 3 ◽  
Tgf Β1

Abstract Purpose: The present study set out to investigate the effect of miR-195-5p on cardiomyocyte apoptosis in rats with heart failure (HF) and its mechanism. Methods: HF rat model and hypoxia/reoxygenation (H/R) cardiomyocyte model were established. miR-195-5p expression and transforming growth factor-β1 (TGF-β1)/signal transduction protein (Smad)3 signaling pathway in HF rats and H/R cardiomyocytes were interfered. miR-195-5p expression was tested by Rt-PCR, TGF-β1/Smad3 signaling pathway related proteins were detected by Western Blot, apoptosis of HF rat cardiomyocytes was tested by TUNEL, and apoptosis of cardiomyocytes induced by H/R was checked by flow cytometry. Results: miR-195-5p was lowly expressed in myocardium of HF rats, while TGF-β1 and Smad3 proteins were high-expressed. Up-regulating miR-195-5p expression could obviously inhibit cardiomyocyte apoptosis of HF rats, improve their cardiac function, and inhibit activation of TGF-β1/Smad3 signaling pathway. Up-regulation of miR-195-5p expression or inhibition of TGF-β1/Smad3 signaling pathway could obviously inhibit H/R-induced cardiomyocyte apoptosis. Dual-luciferase reporter enzyme verified the targeted relationship between miR-195-5p and Smad3. Conclusion: miR-195-5p can inhibit cardiomyocyte apoptosis and improve cardiac function in HF rats by regulating TGF-β1/Smad3 signaling pathway, which may be a potential target for HF therapy.

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