scholarly journals A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

2020 ◽  
Vol 117 (49) ◽  
pp. 31353-31364
Author(s):  
Lisa K. Mullany ◽  
Aarti D. Rohira ◽  
John P. Leach ◽  
Jong H. Kim ◽  
Tanner O. Monroe ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Interleukin 1 ◽  
Steroid Receptor ◽  
Inflammatory Signaling ◽  
Steroid Receptor Coactivator ◽  
Inflammatory Damage ◽  
Adverse Remodeling ◽  
Steroid Receptor Coactivators

Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion of Tsc22d3-expressing macrophages—all of which may limit inflammatory damage. SRC stimulation with MCB-613 (and derivatives) is a potential therapeutic approach for inhibiting cardiac dysfunction after MI.

scholarly journals A Steroid Receptor Coactivator Stimulator MCB-613 Attenuates Adverse Remodeling After Myocardial Infarction

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A803-A803
Author(s):  
Lisa K Mullany ◽  
Aarti Rohira ◽  
Jong H Kim ◽  
John P Leach ◽  
Andrea Ortiz ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Small Molecule ◽  
Cardiac Dysfunction ◽  
Heart Development ◽  
Tissue Injury ◽  
Cardiac Injury ◽  
Steroid Receptor ◽  
Injury Response ◽  
Adverse Remodeling ◽  
Steroid Receptor Coactivators

Abstract Previous work from ours and other laboratories have shown that steroid receptor coactivators (SRCs) are involved in heart development and in mitigating cardiac dysfunction in cardiac injury models. Members of the p160 SRC family, SRC-1 (NCOA1), SRC-2 (NCOA2/TIF2/GRIP1) and SRC-3 (NCOA3/AIB1/ACTR/pCIP), interact with nuclear receptors and other transcription factors to drive target gene expression by assembling transcriptional coactivator complexes to increase transcription. This indicates a potential for SRC targeting drugs pertinent to cell migration, proliferation and survival-promoting paracrine interactions in cardiac tissue injury responses. We have identified a small molecule activator of SRCs (MCB-613) that selectively and reversibly binds to SRCs as shown by surface plasmon resonance and is a potent SRC stimulator that acts to greatly enhance SRC transcriptional activity with no apparent toxicity in mice. We postulated that MCB-613 could enable wound repair and preservation of cardiac function after an acute MI by reducing the extent of injury-related fibrosis and the subsequent chronic loss of cardiac function associated with non-contracting scar tissue. We thus tested the effect of MCB-613 on the cardiac injury response by administering MCB-613 two hours after ischemic injury in a mouse model of MI. Along with measurements of functional cardiac output and damage, we sought to identify the cell-type specific responses responsible for MCB-613’s cardio-protective effects by utilizing single cell transcriptomics of cardiac interstitial cells to characterize the effects of SRC stimulation on cardiac function post-MI. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post-MI, induces lasting protection from adverse remodeling concomitant with: (i) inhibition of macrophage inflammatory signaling and IL-1 signaling which attenuates the acute inflammatory response, (ii) attenuation of fibroblast differentiation, and (iii) promotion of Tsc22d3 expressing macrophages - all of which may limit inflammatory damage. Our results indicate MCB-613 controls the cellular interstitial cardiac repair response to ischemia. Distinct molecular and cellular mechanisms related to stimulation of SRC-3 have been identified that pave the way for the further exploration of SRCs as drug targets that can be engaged to improve the management of myocardial injury response outcomes. SRC stimulation with MCB-613 (and derivatives) is a potential novel therapeutic approach for inhibiting cardiac dysfunction after MI.

scholarly journals The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction

2020 ◽  
Author(s):  
Liangpeng Li ◽  
Wenbin Fu ◽  
Xue Gong ◽  
Zhi Chen ◽  
Luxun Tang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
G Protein ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Beclin 1 ◽  
Receptor Kinase ◽  
G Protein Coupled

Abstract Aims G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI. Methods and results We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers. Conclusion GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

Abstract 16459: Myocardial Replenishment of Tissue Inhibitor of Metalloproteinase (TIMP)-3 and TIMP4 Following Myocardial Infarction Result in Differential Protective Effects

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Abhijit Takawale ◽  
Ratnadeep Basu ◽  
Xiuhua Wang ◽  
Zamaneh Kassiri
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cellular Response ◽  
Imaging System ◽  
Tissue Injury ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Adverse Remodeling

Introduction: The cardiomyopathy ensuing myocardial infarction (MI) results from the ischemic loss of the myocardium, impaired left ventricular (LV) dilation, eventually leading to heart failure. This is accompanied with adverse remodeling of the extracellular matrix (ECM) and disrupted balance of its regulatory proteins, particularly TIMP3 and TIMP4 that are reduced shortly after MI induction. Hypothesis: Replenishment of TIMP3 and/or TIMP4 post-MI will hinder adverse remodeling of the ECM and may also promote beneficial cellular response to limit tissue injury and cardiac dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad-hTIMP3), human TIMP4 (Ad-hTIMP4) or no-TIMP control (Ad-Null) were injected in the peri-infarct zone (5 injections/heart; 5.4x107 pfu/heart). Cardiac function was assessed by Vevo2100 ultrasound imaging system. Cellular and molecular analyses (inflammation, cell viability, angiogenesis, ECM composition) were assessed at 3 and 7 days post-MI. Results: Injection of Ad-Null had minimal effects in the post-MI dysfunction and remodeling. Ad-hTIMP3 injection exerted more beneficial effects compared to Ad-hTIMP4. Ad-TIMP3 group showed significantly better cardiac function (EF=35.49±2.52%, p<0.05), and to a lesser extent Ad-TIMP4 group (EF=28.79±1.79%) compared to Ad-Null group (EF=25.46±2.29%). Similarly, LV dilation was markedly attenuated in Ad-TIMP3 (LVEDV=77.08±6.05μL) but not in Ad-TIMP4 group (LVED=112.98±5.68 μL) compared to Ad-Null (LVEDV=112.98±7.0 μL). Inflammatory response (macrophage/neutrophil density) was not altered with Ad-TIMP treatment. Interestingly, the infarct size was smaller in Ad-TIMP3 group and even after 1wk post-MI, viable myocytes were detected in these hearts. Assessment of coronary density in the infarct and peri-infarct regions (intra-jugular fluoro-tagged lectin injection) revealed that Ad-TIMP3 promoted angiogenesis in the infarcted myocardium. Conclusions: This novel pro-angiogenic function of TIMP3 post-MI, in addition to its MMP inhibitory function, could provide additional beneficial effects in post-MI treatment.

Abstract 577: Matricryptin p1158/59 Improves Cardiac Function Post-myocardial Infarction by Reducing Adverse Remodeling

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Gabriel A Grilo ◽  
Patti R Shaver ◽  
Rugmani P Iyer ◽  
Lisandra E de Castro Brás
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Post Myocardial Infarction ◽  
Adverse Remodeling

scholarly journals DPP-4 Inhibition Attenuates Cardiac Dysfunction and Adverse Remodeling Following Myocardial Infarction in Rats with Experimental Diabetes

2013 ◽  
Vol 31 (5) ◽  
pp. 259-267 ◽  
Author(s):  
Kim Alexander Connelly ◽  
Yanling Zhang ◽  
Andrew Advani ◽  
Suzanne L. Advani ◽  
Kerri Thai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Experimental Diabetes ◽  
Adverse Remodeling

scholarly journals PO-190 Exercise Training Protects Against Cardiac Pathological Remodeling in Myocardial Infarction rats via Improving Mitochondrial Biogenesis

2018 ◽  
Vol 1 (4) ◽  
Author(s):  
Dandan Jia ◽  
Zhenjun Tian
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Exercise Training ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Mitochondrial Biogenesis ◽  
Cardiac Dysfunction ◽  
Myocardial Apoptosis ◽  
The Impact ◽  
Pathological Remodeling

Objective  Growing evidence suggests that exercise training reverses cardiac pathological remodeling and cardiac dysfunction during myocardial infarction (MI), but the underlying mechanisms have not been fully understood. In this study, we investigated the impact of exercise training on cardiac function, myocardial fibrosis, apoptosis, oxidative stress and mitochondrial biogenesis. Methods Sprague Dawley rats were subjected to MI by permanent ligation of the left anterior descending (LAD) coronary artery or Sham operation. Rats with MI were randomly assigned to sedentary MI group (MI) and MI with exercise training group (MI+EX), and compared to sham-operated group (Sham). Haemodynamics and Masson staining were conducted to evaluate the effect of exercise training on cardiac function and myocardial fibrosis. Myocardial apoptosis, oxidative stress, mitochondrial biogenesis and molecular signaling mechanism were analyzed. Results  Exercise training significantly improves cardiac function and mitigates the MI-induced cardiac pathological remodeling. Meanwhile, Exercise training significantly attenuates MI-induced apoptosis, oxidative stress and mitochondrial biogenesis. In addition, activation of PI3K pathway following MI is further induced by exercise training. Conclusions  Exercise training protects against MI-induced cardiac dysfunction and pathological remodeling through preventing myocardial apoptosis and oxidative stress, and enhancing mitochondrial biogenesis.

scholarly journals Silencing CircHIPK3 Sponges miR-93-5p to Inhibit the Activation of Rac1/PI3K/AKT Pathway and Improves Myocardial Infarction-Induced Cardiac Dysfunction

2021 ◽  
Vol 8 ◽  
Author(s):  
Yijin Wu ◽  
Min Wu ◽  
Jue Yang ◽  
Ying Li ◽  
Wenying Peng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Dysfunction ◽  
Harmful Effect ◽  
Akt Pathway ◽  
Circular Rnas ◽  
Cerna Network ◽  
Myocardial Apoptosis

The ceRNA network involving circular RNAs (circRNAs) is essential in the cardiovascular system. We investigated the underlying ceRNA network involving circHIPK3 in myocardial infarction (MI). After an MI model was established, cardiac function was verified, and myocardial tissue damage in mice with MI was evaluated. A hypoxia model of cardiomyocytes was used to simulate MI in vivo, and the expression of and targeting relationships among circHIPK3, miR-93-5p, and Rac1 were verified. The apoptosis of cardiomyocyte was identified. Gain- and loss-of-functions were performed to verify the ceRNA mechanism. The MI-modeled mice showed cardiac dysfunction and enlarged infarct size. CircHIPK3 was highly expressed in mouse and cell models of MI. Silencing circHIPK3 reduced infarct size, myocardial collagen deposition, and myocardial apoptosis rate and improved cardiac function. CircHIPK3 sponged miR-93-5p, and miR-93-5p targeted Rac1. Overexpression of miR-93-5p inhibited MI-induced cardiomyocyte injury and eliminated the harmful effect of circHIPK3. CircHIPK3 acted as ceRNA to absorb miR-93-5p, thus promoting the activation of the Rac1/PI3K/AKT pathway. We highlighted that silencing circHIPK3 can upregulate miR-93-5p and then inhibit the activation of Rac1/PI3K/Akt pathway, which can improve MI-induced cardiac dysfunction.

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