Simvastatin ameliorates ventricular remodeling via the TGF-β1 signaling pathway in rats following myocardial infarction

Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-β1 (TGF-β1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and Fgf21 knockout (Fgf21 KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-β1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of Fgf21 weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H2O2 (100 μM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H2O2-induced activation of the TGF-β1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-β1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.

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MiR-29b Inhibits Ventricular Remodeling By Activating Notch Signaling Pathway in the Rat Myocardial Infarction Model

The Heart Surgery Forum ◽

10.1532/hsf.2079 ◽

2019 ◽

Vol 22 (1) ◽

pp. E019-E023 ◽

Cited By ~ 3

Author(s):

Yang Liu ◽

Hongliang Wang ◽

Xiudan Wang ◽

Guohong Xie

Keyword(s):

Myocardial Infarction ◽

Notch Signaling ◽

Signaling Pathway ◽

Sham Group ◽

Ventricular Remodeling ◽

Notch Signaling Pathway ◽

Negative Control ◽

Blank Group ◽

Relative Expression ◽

Qrt Pcr

Background: To study the effect of miR-29b on myocardial infarction via Notch signaling pathway in rats. Methods: The rat acute myocardial infarction (AMI) models were established and were divided into AMI group, sham group and normal group (N = 10 in each group). HE (Hemotoxylin and eosin) staining was used to detect whether the model was constructed successfully. MiR-29b mimics, inhibitors, mimics negative control (NC) were transfected into H9c2 (2-1) cells. Then, cells were divided into a mimics group, inhibitor group, NC group, and blank group. The relative expression levels of miR-29b, Notch1, DII4 and Hesl were detected by qRT-PCR. The expression of NICD1 was detected by Western blotting. Results: The rat AMI model was successfully constructed. Compared with normal and sham groups, the miR-29b expression was down-regulated, while the expression of Notch1, DII4 and Hesl was increased, and the NICD1 protein expression was increased in the myocardial infarction area of the AMI group (P < .05). Compared with the NC and blank groups, the relative expression of Notch1, DII4, Hesl and NICD1 were upregulated in the mimics group (P < .05), whereas the expression of Notch1, DII4, Hesl and NICD1 in the inhibitor group was decreased (P < .05). Conclusion: MiR-29b inhibited myocardial fibrosis and cardiac hypertrophy by activating the Notch signaling pathway and protected myocardium against myocardial infarction.

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The protective effects of liguzinediol on congestive heart failure induced by myocardial infarction and its relative mechanism

10.21203/rs.3.rs-18923/v1 ◽

2020 ◽

Author(s):

Qi Chen ◽

Dini Zhang ◽

Yunhui Bi ◽

Weiwei Zhang ◽

Yuhan Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Myocardial Cell ◽

Protective Effects ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Cardiac Functions ◽

Tgf Β1

Abstract Background : Heart failure (HF) is one of the most common causes of cardiovascular diseases in the world. Currently, the drugs used to treat HF in the clinic may cause serious side effects. Liguzinediol, 2, 5-dimethyl-3, 6-dimethyl-pyrazine, is a compound synthesized after the structural modification of ligustrazine (one active ingredient of Szechwan Lovage Rhizome ). We aimed to observe the effects of liguzinediol on preventing HF and explore the related mechanisms. Methods : The ligation of left anterior descending coronary artery was operated to established the myocardial infarction (MI) model in Sprague–Dawley rats. Cardiac functions were recorded by echocardiography and hemodynamics. The changes in the Renin-Angiotensin-Aldosterone System (RAAS), inflammation, and oxidative stress were detected by radioimmunoassay and Elisa kits. Western blot and real-time PCR were applied to determine the expressions of the TGF-β1/Smads pathway. Results : Firstly, liguzinediol enhanced the systolic and diastolic functions of the heart in MI rats. Liguzinediol improved ventricular remodeling by reducing myocardial cell necrosis, as well as reducing collagen deposition and myocardial fibrosis. Then, liguzinediol suppressed the activation of RAAS, inhibited the synthesis of pro-inflammation factors, and reduced oxidative stress. In the end, liguzinediol also down-regulated the expressions of the TGF-β1/Smads pathway. Conclusions : Liguzinediol could alleviate HF caused by MI in rats, and the protective effect was associated with the regulation of the TGF-β1/Smads pathway.

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Effects of Yiqi Huoxue Decoction on Post-Myocardial Infarction Cardiac Nerve Remodeling and Cardiomyocyte Hypertrophy in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5168574 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Hui Wang ◽

Yuqin Zhang ◽

Shuwen Guo ◽

Jiani Wu ◽

Wang’ou Lin ◽

...

Keyword(s):

Myocardial Infarction ◽

Signaling Pathway ◽

Ventricular Remodeling ◽

Myocardial Hypertrophy ◽

Heart Function ◽

Stellate Ganglion ◽

Cardiomyocyte Hypertrophy ◽

H9c2 Cells ◽

Sprague Dawley ◽

Cross Sectional

Myocardial infarction can lead to ventricular remodeling and arrhythmia, which is closely related to nerve remodeling. Our previous study found that Yiqi Huoxue decoction (YQHX) can improve ventricular remodeling and reduce myocardial damage. Therefore, in this study, we observed the effect of YQHX on cardiac neural remodeling and cardiomyocyte hypertrophy and its possible mechanism. This research is composed of two parts: animal and H9c2 cells experiments. The animal model of acute myocardial infarction was established by ligating the left anterior descending coronary artery in Sprague Dawley (SD) rats. H9c2 cells were placed in 94% N2, 5% CO2, and 1% O2 hypoxic environment for 12 hours to replicate the hypoglycemic hypoxia model. The experimental results showed that, compared with the MI group, YQHX can significantly improve heart function after myocardial infarction and reduce nerve remodeling and myocardial hypertrophy. Pathological structure observation demonstrated reducing myocardial tissue damage and decreasing of cell cross-sectional area, diameter, and circumference. The positive rate of TH declined apparently, and the sympathetic nerve density was lower than that of the MI group. After YQHX was given for 28 days, the proneural remodeling factors TH, NGF, and GAP43 in the marginal zone of infarction and stellate ganglion decreased obviously while the inhibitory nerve remodeling factor Sema-3A increased. The myocardial hypertrophic protein ANP and β-MHC were also significantly inhibited with p-ERK1/2 protein expression level prominently reduced. There was no difference between the YQHX group and the Meto group. After myocardial infarction, nerve remodeling was seen in the marginal area of infarction and stellate ganglion, and the neuropeptides released by which promoted myocardial hypertrophy. The mechanism may be related to the ERK1/2 signaling pathway. YQHX could regulate the ERK1/2 signaling pathway, inhibit the release of nerve remodeling factors and myocardial hypertrophy protein to reduce nerve remodeling, and relieve myocardial hypertrophy.

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Inhibition of TGF-β1 signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through angiogenesis and reduction of apoptosis

Cardiovascular Pathology ◽

10.1016/j.carpath.2007.02.007 ◽

2007 ◽

Vol 16 (4) ◽

pp. 221-230 ◽

Cited By ~ 31

Author(s):

Lei-Lei Chen ◽

Hang Yin ◽

Jun Huang

Keyword(s):

Myocardial Infarction ◽

Gene Transfer ◽

Ventricular Remodeling ◽

Enos Gene ◽

Tgf Β1

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Activation of TGF-β1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00186.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. H709-H715 ◽

Cited By ~ 81

Author(s):

Madoka Matsumoto-Ida ◽

Yoshihito Takimoto ◽

Takeshi Aoyama ◽

Masaharu Akao ◽

Toshihiro Takeda ◽

...

Keyword(s):

Myocardial Infarction ◽

P38 Mapk ◽

Ventricular Hypertrophy ◽

Ventricular Remodeling ◽

Mapk Pathway ◽

Left Ventricular ◽

Kinase Assay ◽

Causative Role ◽

P38 Mapk Pathway ◽

Tgf Β1

Transforming growth factor-β1 (TGF-β1) alters myocardial gene expression, resulting in myocyte hypertrophy, through activation of TGF-β-activated kinase (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family. We hypothesized that the TGF-β1-TAK1-p38 MAPK pathway might be activated during ventricular remodeling after myocardial infarction (MI). One, 3, 7, and 14 days after ligation of the left anterior descending coronary artery, noninfarcted left ventricular tissue samples were obtained. Protein levels as well as mRNA levels of the signaling pathway, TGF-β1, TGF-β-receptors, and TAK1 increased in the noninfarcted myocardium in MI rats compared with sham-operated animals. Phosphorylation of MAPKK 3/6 (MKK3/6) and p38 MAPK, the downstream targets of TAK1, was also increased in the noninfarcted region. Moreover, an in vitro kinase assay revealed that the activated TAK1 in the noninfarcted myocardium was capable of activating recombinant MKK3/6, suggesting a causative role of TAK1 in the remodeling process. The activation of the TGF-β1-TAK1-p38 MAPK pathway paralleled the transcriptional upregulation of cardiac markers for ventricular hypertrophy, β-myosin heavy chain and atrial natriuretic peptide. TAK1 was mainly localized to cardiomyocytes, whereas TGF-β1 receptors were observed in vascular smooth muscle cells and fibroblasts as well as cardiomyocytes. Thus the TGF-β1-TAK1-MKK3/6-p38 MAPK pathway in the cardiomyocytes of noninfarcted spared myocardium is activated after acute MI and may play an important role in ventricular hypertrophy and post-MI remodeling in rats.

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