Stathmin 1 Attenuates the Myocardial Fibrosis in Rat Model of Heart Failure.

IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure

Long noncoding RNA SOX2OT is associated with myocardial fibrosis (MF) in heart failure (HF). This article aims to investigate the role of SOX2OT in MF. We constructed HF mouse models by subcutaneous injection of isoprenaline (ISO). Cardiac fibroblasts (CFs) were treated with ISO to induce MF.Hematoxylin-eosin, Masson, and Sirius-red staining were used to identify myocardial injury and collagen deposition in heart tissues. The relationship among SOX2OT, miR-138-5p, TGF-β1, and Smad3 were evaluated by chromatin immunoprecipitation and luciferase reporter assay. The gene and protein expression were verified by quantitative real-time PCR and western blot. We found that SOX2OT was up-regulated in HF mice and ISO-induced CFs. SOX2OT knockdown reduced myocardial injury and collagen deposition in HF mice. The expression of collagen I, α-SMA, TGF-β1, and p-Smad3 were inhibited by SOX2OT down-regulation in HF mice and ISO-induced CFs. Furthermore, TGF-β1 was a target gene of miR-138-5p and indirectly regulated by SOX2OT. SOX2OT promoted MF in HF by activating TGF-β1/Smad3, and then Smad3 interacted with the SOX2OT promoter and formed a positive feedback loop. In conclusion, our work verifies that SOX2OT/Smad3 feedback loop promotes MF in HF. Thus, SOX2OT is potentially a novel therapeutic target for MF in HF.

What is the central question of this study? Does the advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE) axis mediate myocardial fibrosis in heart failure? What is the main finding and its importance? The AGEs-RAGE axis is involved in the pathogenesis of myocardial fibrosis through activation of cardiac fibroblasts induced by autophagy in heart failure. By suppression of cardiac fibroblast activation, inhibition of the AGEs-RAGE axis attenuates cardiac dysfunction and myocardial fibrosis in mice with transverse aortic constriction. Heart failure is the end stage of cardiovascular disease and is a critical medical condition that poses an important therapeutic challenge for physicians owing to its high morbidity and mortality. Myocardial fibrosis is part of the remodelling process that occurs in heart failure. Many studies have shown that advanced glycation end products (AGEs) and receptor for advanced glycation end products (RAGE) are implicated in fibrosis and autophagy, but the mechanism remains unclear. In this study, we elucidated the mechanism by which the AGEs-RAGE axis mediates activation of cardiac fibroblasts (CFs) in heart failure. We used C57BL/6J wild-type (WT) mice to establish a model of heart failure by transverse aortic constriction (TAC). After 6weeks of treatment, relevant indicators were detected. In mice subjected to TAC, AGEs were upregulated compared with sham-operated mice. Inhibition of RAGE resulted in functional cardiac protection, with reduced hypertrophy and fibrosis in mice after TAC. Of note, autophagy mediated the activation of CFs that transformed to myofibroblasts and contributed to fibrosis. In vitro, CFs were obtained from neonatal Sprague-Dawley rats and treated with AGEs, bovine serum albumin and short hairpin RNA (shRNA) for RAGE, in order to verify the results obtained in vivo. These results suggest that the AGEs-RAGE axis is involved in the pathogenesis of myocardial fibrosis in heart failure through CF activation induced by autophagy. Inhibition of the AGEs-RAGE axis attenuates cardiac dysfunction and myocardial fibrosis in mice with TAC by suppressing CF activation.

Optimized new Shengmai powder ameliorates myocardial fibrosis in rats with heart failure by inhibition of the MAPK signaling pathway

In the myocardium, collagen fibers provide a supporting framework for myocytes and blood vessels and act as lateral connections between muscle bundles. These functional properties of collagen serve to maintain tissue architecture and to coordinate the delivery of force generated by myocytes on the ventricular chamber. The accumulation of excess collagen is believed to be an important pathophysiological process that contributes to diastolic heart failure. Diastolic heart failure accounts for 30% to 50% of heart failure in clinical practice, and hypertensive disease is the major cause of this type of heart failure.1 The precise mechanisms responsible for excess fibrillar collagen accumulation in the pathological heart are poorly understood. Fibrosis of both the injured and noninjured myocardium2 indicates that humoral mechanisms are responsible for this process. In the failing heart, several humoral, autocrine, and paracrine systems are activated,3 suggesting that cross-talk between synergistic and opposing signaling pathways constitutes the predominant form of regulation under these conditions. Several factors have been identified as potentially important mediators of cardiac collagen production. In vitro studies of neonatal and adult rat cardiac fibroblasts have shown that angiotensin II (Ang II) directly stimulates cardiac fibroblast proliferation and collagen synthesis via Ang II type 1 (AT1) receptors.4 5 6 In this issue of Hypertension , Pathak et al7 provided evidence that a myocyte cofactor was an important mediator of Ang II–induced collagen type I and type III mRNA synthesis in a rat cell coculture model. This work, together with other studies, provides strong evidence that Ang II indirectly regulates cardiac fibroblast function via specific growth factors.8 9 10 11 12 13 14 15 16 17 18 19 20 21 Although the primary autocrine and paracrine mediators of Ang II effects on fibrillar collagen synthesis remain to be elucidated, principal candidates …

Objectives: The impact of high thoracic sympathetic block (HTSB) on myocardial fibrosis in chronic heart failure (HF) is unclear. Myocardial collagen synthesis can be assessed by measuring circulating biomarkers. We observed the effect of HTSB on serum collagen biomarkers in HF. Methods: Forty-four patients were randomized to a control and a HTSB group. They received routine medications. Repeated epidural injections were given to the HTSB group for 4 weeks. Echocardiography and measurements of serum carboxy-terminal propeptide of procollagen type I (PICP) and amino-terminal propeptide of procollagen type III (PIIINP) were performed at baseline and 4 weeks later. Results: There were significant reductions in left atrial diameter, left ventricular (LV) diameter and volume, LV weight index (LVWI) and serum PICP and PIIINP levels in the HTSB group (p < 0.05). The changes in LV end-systolic volume and ejection fraction (LVEF) were greater in the HTSB group than in the control group (p < 0.05). In the HTSB group, the decreases in PICP and PIIINP were correlated with the decrease in LVWI (PICP: r = 0.695, p = 0.000; PIIINP: r = 0.642, p = 0.001), and the decrease in PICP was negatively associated with the rise in LVEF (r = -0.813, p = 0.000). Conclusion: HTSB reduces myocardial fibrosis in HF, which may accompany the improvement of LV hypertrophy and dysfunction.

Heart failure is the terminal stage of cardiovascular disease, and its pathological mechanism is ventricular remodeling. Therefore, the fundamental of preventing and treating heart failure is to inhibit ventricular remodeling. The important link of ventricular remodeling is myocardial fibrosis. It can prevent and cure heart failure by inhibiting the occurrence of myocardial fibrosis. By querying relevant domestic and foreign literatures in recent years, it was found that TGF-β/Smad signaling pathway plays an important role in the development of myocardial fibrosis, it may reduce cell damage through anti-inflammatory, antioxidant stress, anti-apoptosis, etc., Maintaining extracellular matrix stability, alleviate the degree of myocardial fibrosis, Chinese medicine in the prevention and treatment of fibrosis has high efficacy, multi-target, improve long-term prognosis and other advantages. To explore a more accurate target drug for preventing and treating myocardial fibrosis in heart failure, reduce the rate of readmission of patients with heart failure, and provide a greater possibility for promoting the prevention and treatment of myocardial fibrosis in heart failure by traditional Chinese medicine.

BackgroundInterstitial fibrosis and fibrotic scar formation contribute to cardiac remodeling and loss of cardiac function in myocardial infarction (MI) and heart failure. Recent studies showed that histone deacetylase (HDAC) inhibitors retard fibrosis formation in acute MI settings. However, it is unknown whether HDAC inhibition can reverse cardiac fibrosis in ischemic heart failure. In addition, specific HDAC isoforms involved in cardiac fibrosis and myofibroblast activation are not well defined. Thus, the purpose of this study is to determine the effects of selective class I HDAC inhibition on cardiac fibroblasts activation and cardiac fibrosis in a congestive heart failure (CHF) model secondary to MI.MethodsMI was created by left anterior descending (LAD) coronary artery occlusion. Class I HDACs were selectively inhibited via Mocetinostat in CD90+ fibroblasts isolated from atrial and ventricular heart tissue in vitro. In vivo, Class I HDACs were inhibited in 3 weeks post MI rats by injecting Mocetinostat for the duration of 3 weeks. Cardiac function and heart tissue were analyzed at 6 weeks post MI.ResultsIn sham hearts, HDAC1 and HDAC2 displayed differential expression patterns where HDAC1 mainly expressed in cardiac fibroblast and HDAC2 in cardiomyocytes. On the other hand, we showed that HDAC1 and 2 were upregulated in CHF hearts, and were found to co-localize with CD90+ cardiac fibroblasts. In vivo treatment of CHF animals with Mocetinostat improved left ventricle end diastolic pressure and dp/dt max and decreased the total collagen amount. In vitro treatment of CD90+ cells with Mocetinostat reversed myofibroblast phenotype as indicated by a decrease in α-Smooth muscle actin (α-SMA), Collagen III, and Matrix metalloproteinase-2 (MMP2). Furthermore, Mocetinostat increased E-cadherin, induced β-catenin localization to the membrane, and reduced Akt/GSK3β signaling in atrial cardiac fibroblasts. In addition, Mocetinostat treatment of atrial CD90+ cells upregulated cleaved-Caspase3 and activated the p53/p21 axis.ConclusionsTaken together, our results demonstrate upregulation of HDAC1 and 2 in CHF. In addition, HDAC inhibition reverses interstitial fibrosis in CHF. Possible anti-fibrotic actions of HDAC inhibition include reversal of myofibroblast activation and induction of cell cycle arrest/apoptosis.

BackgroundOptimized New Shengmai Powder (ONSMP) is a traditional Chinese medicine formula with significant anti-heart failure and myocardial fibrosis effects, but the specific molecular biological mechanisms are not fully understood.MethodsIn this study, we first used network pharmacology to analyze the ONSMP's active ingredients, core signaling pathways, and core targets. Second, calculate the affinity and binding modes of the ONSMP components to the core targets using molecular docking. Finally, the heart failure rat model was established by ligating the left anterior descending branch of the coronary artery and assessing the effect of ONSMP on myocardial fibrosis in heart failure using echocardiography, cardiac organ coefficients, heart failure markers, and pathological sections after 4 weeks of drug intervention. The cAMP level in rat myocardium was determined using Elisa, the α-SMA and FSP-1 positive expression determined by immunohistochemistry, and the protein and mRNA levels of the cAMP/Rap1A signaling pathway were detected by Western Blotting and quantitative real-time PCR, respectively.ResultsThe result shows that the possible mechanism of ONSMP in reducing myocardial fibrosis also includes the use of 12 active ingredients such as baicalin, vitamin D, resveratrol, tanshinone IIA, emodin, 15,16-dihydrotanshinone-i to regulate β1-AR, AC6, EPAC1, Rap1 A, STAT3, and CCND1 on the cAMP/Rap1A signaling pathway, thereby inhibiting the proliferation of cardiac fibroblasts and reduce the excessive secretion of collagen, effectively improve cardiac function and ventricular remodeling in heart failure rats.ConclusionThis research shows that ONSMP can inhibit myocardial fibrosis and delay heart failure through the cAMP/Rap1A signaling pathway.

BackgroundThis study aimed to explore the effects of Kangdaxin oral liquid on myocardial fibrosis in heart failure with preserved ejection fraction (HFpEF) rats.MethodsA total of 30 Sprague Dawley (SD) rats were randomly divided into 3 groups Sham operation group (Sham), HFpEF group (HFpEF), and HFpEF with drug intervention group (HFpEF + I). Rats in HFpEF + I group were given Kangdaxin oral liquid at a dose of 2.7 mL/(kg·d). After modeling or treatment, the value of E/A and E/e' in each group of rats were measured by echocardiography. The N-terminal pro b-type natriuretic peptide (NT-proBNP) level was determined by enzyme-linked immunosorbent assay (ELISA). Heart weight/body mass index (Hw/W) and left ventricular weight/body mass index (LVw/W) were calculated after the rats were sacrificed; the transforming growth factor-β1 (TGF-β1) protein expression level in cardiac tissue was detected by western blot.ResultsCompared with sham group, the values of diastolic function item (E/A) and mitral annular early diastolic velocity (E/e') in HFpEF group were significantly decreased, and the level of NT-proBNP was significantly increased (P<0.05). Compared with HFpEF group, the value of E/A and E/e' in HF + I group were significantly increased, and the level of NT-proBNP was significantly decreased (P<0.05). Compared with sham group, the expression of TGF-β1 protein in heart tissue of HFpEF group were significantly increased (P<0.05). Compared with HFpEF group, the expression of TGF-β1 protein in HFpEF + I group were significantly decreased (P<0.05).ConclusionsKangdaxin oral liquid has protective effect on heart in HFpEF rats, which can reduce the protein expression of TGF-β1 in the heart tissue of HFpEF rats. This may be a possible mechanism to inhibit myocardial fibrosis and improve cardiac diastolic function.

Vascular Dysfunction in Heart Failure with Preserved Ejection Fraction

Optimized new Shengmai powder inhibits myocardial fibrosis in heart failure by regulating the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway.

See related article, pages 113–123 Cardiac hypertrophy is often accompanied by cardiac remodeling characterized by loss of cardiac myocytes, interstitial fibroblasts, and collagen deposition, leading to decreased ventricular compliance and an increased risk for heart failure. The mortality for patients with heart failure is still high, although some improvements have been demonstrated in patients with systolic heart failure.1–3 To improve the therapeutic strategy for patients with heart failure, especially diastolic heart failure, further research and investigations to better understand the molecular and biochemical mechanism are needed. Serotonin (5-hydroxytryptamine [5-HT]) affects many physiological functions through the interaction with specific G-coupled membrane receptors, 5-HT receptors. There are 4 classes of 5-HT receptors (5-HT1/5, 5-HT2, 5-HT3, and 5-HT4/6/7).4 Serotonin, via the 5-HT2B receptor, regulates cardiac development and function.5 Transgenic mice with a 5-HT2B receptor gene ablation show embryonic and neonatal death caused by lack of trabeculae in the heart.6 5-HT2B receptors are essential for isoproterenol-induced cardiac hypertrophy, which involves the regulation of interleukin-6, interleukin-1β, and tumor necrosis factor-α cytokine production by cardiac fibroblasts.7 The 5-HT2B receptor has been shown functionally coupled to reactive oxygen species synthesis through NAD(P)H oxidase stimulation in neuronal cells8 and in angiotensin II and isoproterenol-induced cardiac hypertrophy.9 Recently, 5-HT2B receptor blockade has been shown to prevent the cardiac hypertrophy induced by angiotensin II or isoproterenol infusion.9 …

Calycosin reduces myocardial fibrosis and improves cardiac function in post-myocardial infarction mice by suppressing TGFBR1 signaling pathways

Buyang Huanwu Decoction suppresses cardiac inflammation and fibrosis in mice after myocardial infarction through inhibition of the TLR4 signalling pathway