Pharmacological inhibition of SUMO-1 with ginkgolic acid alleviates cardiac fibrosis induced by myocardial infarction in mice

2018 ◽  
Vol 345 ◽  
pp. 1-9 ◽  
Author(s):  
Fang Qiu ◽  
Changjiang Dong ◽  
Yanxin Liu ◽  
Xiaoqi Shao ◽  
Di Huang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
Pharmacological Inhibition ◽  
Ginkgolic Acid

scholarly journals Pharmacological Inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis in Mice Cardiac Fibroblast and Post-Myocardial-Infarction Models

2015 ◽  
Vol 37 (2) ◽  
pp. 515-526 ◽  
Author(s):  
Guang-Pu Fan ◽  
Wei Wang ◽  
Hui Zhao ◽  
Lin Cai ◽  
Pei-De Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Heart Function ◽  
Smooth Muscle Actin ◽  
Post Myocardial Infarction ◽  
Type I ◽  
Pharmacological Inhibition

Background: To investigate the role of focal adhesion kinase (FAK)-mediated signaling in hypoxia-induced cardiac fibroblasts (CFs) differentiation and cardiac fibrosis post-myocardial infarction (MI) on a mice model. Methods: CFs of neonatal C57BL/6 mice were treated under normoxic, hypoxic, or hypoxic+PP2 (known as a Src kinase family inhibitor) conditions. Gene expressions of FAK, alpha-smooth muscle actin (α-SMA) and collagen type I alpha 1 (Col1α1), or α-SMA and vimentin levels were performed by RT-PCR and immunofluorescence staining, respectively. Thirty mice were surgically treated into Sham (n=7) and MI (n=23) groups; and FAK inhibitor PF-562271 was given to six survivor MI mice (as PF group, from 15 survivors). Heart function and collagenous tissues were examined by echocardiography, as well as by Masson‘s trichrome and Sirius red staining, respectively. Type I collagen, FAK protein, mTOR, ERK1/2, AKT, P70S6K and phospho-FAK levels were also analyzed. Results: FAK inhibition with PP2 significantly decreased CFs differentiation and collagen synthesis under hypoxia treatment. In vivo, PF-562271 treatment resulted in fibrosis attenuation; however, deteriorated heart function of MI mice could not be significantly improved. PF-562271 may affect phospho-mTOR (p<0.05), phospho-ERK1/2 (p<0.01), phospho-AKT (p<0.001) and phospho-P70S6K (p<0.05) to exert its benefits. FAK can be activated either under hypoxia in CFs or MI in a mouse model to promote fibrosis. However, pharmacological inhibition of FAK can attenuate fibrosis response. Conclusion: This study provides novel evidence that FAK inhibition may become a promising pharmaceutical strategy to attenuate fibrosis post-MI.

Cardiac-specific ablation of theSTAT3gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling

2015 ◽  
Vol 309 (3) ◽  
pp. H471-H480 ◽  
Author(s):  
Daichi Enomoto ◽  
Masanori Obana ◽  
Akimitsu Miyawaki ◽  
Makiko Maeda ◽  
Hiroyuki Nakayama ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Biological Significance ◽  
Weight Ratio ◽  
Fluorescence Analysis ◽  
Border Zone ◽  
Intrinsic Activity ◽  
Heart Weight ◽  
Subacute Phase

STAT3 is a cardioprotective molecule against acute myocardial injury; however, recent studies have suggested that chronic STAT3 activation in genetically modified mice was detrimental after myocardial infarction (MI). In the present study, we assessed the biological significance of STAT3 activity in subacute MI using tamoxifen (TM)-inducible cardiac-specific STAT3 knockout (STAT3 iCKO) mice. After coronary ligation, STAT3 was rapidly activated in hearts, and its activation was sustained to the subacute phase. To make clear the pathophysiological roles of STAT3 activation specifically in subacute MI, MI was generated in STAT3 iCKO mice followed by TM treatment for 14 consecutive days beginning from day 11 after MI, which ablated the STAT3 gene in the subacute phase. Intriguingly, mortality was increased by TM treatment in STAT3 iCKO mice, accompanied by an increased heart weight-to-body weight ratio. Masson's trichrome staining demonstrated that cardiac fibrosis was dramatically exacerbated in STAT3 iCKO mice 24 days after MI (fibrotic circumference: 58.3 ± 6.7% in iCKO mice and 40.8 ± 9.3% in control mice), concomitant with increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. Echocardiography clarified that cardiac function was deteriorated in STAT3 iCKO mice (fractional shortening: 20.6 ± 4.1% in iCKO mice and 29.1 ± 6.0% in control mice). Dihydroethidium fluorescence analysis revealed that superoxide production was increased in STAT3 iCKO mice. Moreover, immunohistochemical analyses revealed that capillary density was decreased in STAT3 iCKO mice. Finally, STAT3 deletion in subacute MI evoked severe cardiac hypertrophy in the border zone. In conclusion, the intrinsic activity of STAT3 in the myocardium confers the resistance to cardiac remodeling in subacute MI.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

scholarly journals Blockade of the Notch Signaling Pathway Promotes M2 Macrophage Polarization to Suppress Cardiac Fibrosis Remodeling in Mice With Myocardial Infarction

2022 ◽  
Vol 8 ◽  
Author(s):  
Zhi Li ◽  
Miao Nie ◽  
Liming Yu ◽  
Dengshun Tao ◽  
Qiang Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cardiac Fibrosis ◽  
Macrophage Polarization ◽  
Notch Signaling Pathway ◽  
Inflammatory Factors ◽  
M2 Macrophage ◽  
M2 Polarization

Myocardial infarction (MI) is regarded as a serious ischemic heart disease on a global level. The current study set out to explore the mechanism of the Notch signaling pathway in the regulation of fibrosis remodeling after the occurrence of MI. First, experimental mice were infected with recombination signal binding protein J (RBP-J) shRNA and empty adenovirus vector, followed by the establishment of MI mouse models and detection of cardiac function. After 4 weeks of MI, mice in the sh-RBP-J group were found to exhibit significantly improved cardiac function relative to the sh-NC group. Moreover, knockdown of RBP-J brought about decreased infarct area, promoted cardiac macrophages M2 polarization, reduced cardiac fibrosis, and further decreased transcription and protein expressions of inflammatory factors and fibrosis-related factors. Furthermore, downregulation of cylindromatosis (CYLD) using si-CYLD reversed the results that knockdown of RBP-J inhibited fibrogenesis and the release of inflammatory factors. Altogether, our findings indicated that the blockade of Notch signaling promotes M2 polarization of cardiac macrophages and improves cardiac function by inhibiting the imbalance of fibrotic remodeling after MI.

scholarly journals Snail1 is involved in de novo cardiac fibrosis after myocardial infarction in mice

2012 ◽  
Vol 44 (11) ◽  
pp. 902-910 ◽  
Author(s):  
Y. Liu ◽  
J. Du ◽  
J. Zhang ◽  
M. Weng ◽  
X. Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
De Novo

scholarly journals Cardiomyocyte Derived miR-328 Promotes Cardiac Fibrosis by Paracrinely Regulating Adjacent Fibroblasts

2018 ◽  
Vol 46 (4) ◽  
pp. 1555-1565 ◽  
Author(s):  
Dandan Zhao ◽  
Cui Li ◽  
He Yan ◽  
Tianyu Li ◽  
Ming Qian ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Coronary Artery ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Collagen Deposition ◽  
Paracrine Signaling ◽  
Potential Therapeutic Target ◽  
Transmission Electron ◽  
Elevated Expression ◽  
Tgf Β1

Background/Aims: In our previous study, we demonstrated that elevated expression of miR-328 is a potent determinant of cardiac fibrosis during myocardial infarction (MI). In the present study, histological examination revealed progressive fibrosis in transgenic mice overexpressing cardiomyocyte-specific miR-328. This study investigated whether the transfer of miR-328 from cardiomyocytes (CMs) to cardiac fibroblasts (CFs) in a paracrine manner contributes to myocardial fibrosis. Methods: Myocardial infarction was established by the occlusion of the left coronary artery. Masson’s trichrome staining and collagen assays were used to evaluate the progression of fibrosis. The vesicles and translocation of miR-328 in a co-culture assay system were respectively observed using transmission electron microscopy (TEM) and immunofluorescence staining (IF). Real-time PCR was employed to detect the level of miR-328, Col1α1 and Col3α1. The protein expression of Col1α1, TGF-βRIII, p-smad2/3 (phosphorylated-smad2/3) and TGF-β1 were probed using western blot analysis. Results: Cardiomyocyte-specific miR-328 overexpressing transgenic (TG) mice showed enhanced collagen deposition and provoked cardiac fibrosis by the activation of the TGF-β1 pathway, and this effect was abrogated after knockdown of endogenous miR-328 in mice. Correspondingly, the expression of miR-328 was increased in CFs co-cultured with CMs transfected with miR-328 mimics, likely in a paracrine manner. The cardiomyocyte-mediated augmentation of miR-328 contributes to fibrogenesis in CFs, and this pro-fibrotic effect was reversed after the transfection of miR-328 inhibitor in CFs. Conclusion: A novel molecular mechanism for miR-328 derived from CMs as a paracrine signaling mediator of cardiac fibrogenesis further demonstrates that miR-328 is a potential therapeutic target.

Abstract 866: Secreted Frizzled Related Protein 2 Modulates Post Myocardial Infarct Remodeling by Inhibiting Collagen Maturation through the Inhibition of Bone Morphogenetic Protein 1 Activity

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Wei He ◽  
Lunan Zhang ◽  
Richard E Pratt ◽  
Victor J Dzau
Keyword(s):  
Myocardial Infarction ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Myocardial Infarct ◽  
Primary Cultures ◽  
The United States ◽  
Coronary Artery Ligation ◽  
Related Protein ◽  
Artery Ligation

Myocardial infarction and post-infarction remodeling with heart failure are the major cause of mortality and morbidity in the United States. We recently reported that intracardiac implantation of genetically engineered mesenchymal stem cell (MSC) overexpressing the Akt gene dramatically reduced the infarct size and restored cardiac functions in rodent hearts after coronary artery ligation. Further, we identified Secreted Frizzled Related Protein 2 (sfrp2) as a key factor released by Akt-MSC mediating myocardial survival and repair. However, the underlying mechanism remains elusive. Bone Morphogenetic Protein1 (BMP1)/Tolloid (TLD)-like metalloproteinases belong to a subgroup of astacin family and play key roles in the regulation of extracelluar matrix (ECM) formation and cardiac fibrosis. These proteases have procollagen C-proteinase (PCP) activities which are responsible for the cleavage of C-propeptides from procollagen precursors to produce mature collagen fibrils. In this report, we showed that three days following myocardial infarction in rats, both BMP1 protein expression and activity were upregulated in the infarcted left ventricle. Interestingly, we found recombinant sfrp2 could inhibit BMP1 activity in MI tissue samples as measured by an in vitro PCP activity assay. Furthermore, using purified recombinant proteins, we demonstrated that sfrp2, but not sfrp1 or sfrp3, inhibited BMP-1 activity in vitro. Moreover, purified sfrp2 could physically interact with BMP1 protein as shown by the co-immunoprecipitation assay. To provide further evidence that sfrp2 can interfere with collagen processing, we demonstrated that exogenously added sfrp2 interfered with procollagen processing in primary cultures of cardiac fibroblast culture medium. Similar results were obtained when these cells were transiently transfected with sfrp2 expressing plasmids. In summary, our data suggest that one of the molecular mechanisms underlying the cardioprotective and repair effects of sfrp2 protein on myocardial infarction is through the inhibition of BMP-1 activity. Therefore, sfrp2 has the potential clinical application as a novel anti-fibrotic reagent for the modulation of cardiac remodeling after acute myocardial infarction.

Abstract 327: Apelin-13 Increases Myocardial Progenitor Cells and Improves Myocardial Remodeling of Post-myocardial Infarction.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
lanfang Li ◽  
Heng Zeng ◽  
Jian-Xiong Chen
Keyword(s):  
Myocardial Infarction ◽  
Progenitor Cells ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cxcr4 Expression ◽  
Post Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Vascular Progenitor Cells

ABSTRACT: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and has beneficial effects against hypertension and myocardial ischemia/reperfusion injury. Little is known about the role of apelin in the homing of vascular progenitor cells (PCs) and cardiac remodeling post-myocardial infarction (MI). The present study investigates whether apelin affects PCs homing to the infarcted myocardium thereby mediating cardiac remodeling post-MI. Mice were infarcted by coronary artery ligation and apelin-13 (1 mg/kg.d) was injected for three days prior to MI and for either 24 hours or 14 days post MI. Homing of vascular progenitor cell (CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and CD133 + /CXCR4 + ) into the ischemic area were examined at 24 hours and 14 days post-MI. Myocardial Akt, eNOS, VEGF, Jagged1, Notch3, SDF-1α and CXCR4 expression were assessed. Functional analyses were performed at day 14 after MI. Mice receiving apelin-13 treatment demonstrated upregulation of SDF-1α/CXCR4 expression and dramatically increased the number of CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and c-kit + /CXCR4 + cells in the infarcted hearts. Apelin-13 also significantly increased Akt and eNOS phosphorylation and upregulated VEGF, Jagged1, Notch3 expression in the ischemic hearts. This was accompanied by a significant reduction of myocardial apoptosis. Further, treatment with apelin-13 promoted myocardial angiogenesis, attenuated cardiac fibrosis and hypertrophy together with a significant improvement of cardiac function at 14 days post-MI mice. Apelin-13 increases angiogenesis and improves cardiac remodeling by a mechanism involving upregulation of SDF-1α/CXCR4 and homing of vascular progenitor cells.

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