Cardiac cAMP-PKA Signaling Compartmentalization in Myocardial Infarction

Under physiological conditions, cAMP signaling plays a key role in the regulation of cardiac function. Activation of this intracellular signaling pathway mirrors cardiomyocyte adaptation to various extracellular stimuli. Extracellular ligand binding to seven-transmembrane receptors (also known as GPCRs) with G proteins and adenylyl cyclases (ACs) modulate the intracellular cAMP content. Subsequently, this second messenger triggers activation of specific intracellular downstream effectors that ensure a proper cellular response. Therefore, it is essential for the cell to keep the cAMP signaling highly regulated in space and time. The temporal regulation depends on the activity of ACs and phosphodiesterases. By scaffolding key components of the cAMP signaling machinery, A-kinase anchoring proteins (AKAPs) coordinate both the spatial and temporal regulation. Myocardial infarction is one of the major causes of death in industrialized countries and is characterized by a prolonged cardiac ischemia. This leads to irreversible cardiomyocyte death and impairs cardiac function. Regardless of its causes, a chronic activation of cardiac cAMP signaling is established to compensate this loss. While this adaptation is primarily beneficial for contractile function, it turns out, in the long run, to be deleterious. This review compiles current knowledge about cardiac cAMP compartmentalization under physiological conditions and post-myocardial infarction when it appears to be profoundly impaired.

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

Circulation ◽

10.1161/circ.132.suppl_3.16459 ◽

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.

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Abstract 75: Ischemic Heart Failure is Exacerbated in CD39-null Mice

Circulation Research ◽

10.1161/res.117.suppl_1.75 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Tatiana Novitskaya ◽

Debra G Wheeler ◽

Zhaobin Xu ◽

Elena Chepurko ◽

Bo Zhang ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Diastolic Pressure ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Smooth Muscles ◽

Left Ventricular ◽

Cardiac Performance ◽

Coronary Artery Ligation ◽

Genetic Ablation

Background: CD39 (ectonucleoside triphosphate diphosphohydrolase) is a nucleotidase expressed on endothelial cells, vascular smooth muscles cells, and leukocytes. CD39 plays a key role in vascular homeostasis, hydrolyzing extracellular ATP and ADP. CD39 has been shown to be important in models of ischemic preconditioning and cardiac ischemia reperfusion. However, the effect of CD39 activity on functional recovery of heart after myocardial infarction (MI) has not been evaluated. Hypothesis: Genetic ablation of CD39 expression exacerbates post-myocardial infarction cardiac function and fibrosis. Methods: Wild-type (WT) and CD39-null mice were subjected to coronary artery ligation. Cardiac function and protein evaluation of fibrotic markers was performed at day 28 post-MI. Results: Evaluation at Day 28 post-MI revealed that while mice of both genotypes had similarly reduced ejection fraction and equally compromised contractile function (dP/dtmax), there was a more pronounced negative effect on lusitropy (dP/dtmin) and increased left ventricular end-diastolic pressure in CD39-null mice. Therefore, cd39 gene ablation associates with the development of worsening cardiac performance. Histological analysis revealed increased collagen deposition and abundance of alpha-smooth muscle actin (αSMA) positive interstitial cells in the CD39-null hearts compared to WT hearts. To quantify these findings immunoblot analysis for collagen and αSMA was performed. We found that collagen and αSMA were increased at Day 28 post-MI, in CD39-null hearts compared to WT hearts. Conclusion: CD39 ablation has detrimental effects on post-MI recovery, resulting in diminished cardiac performance and increased fibrosis.

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Faculty Opinions recommendation of Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13945983.15401088 ◽

2012 ◽

Author(s):

Anthony Dart

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Function Structure ◽

Type Vi Collagen

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Author Correction: In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0271-x ◽

2019 ◽

Vol 51 (9) ◽

pp. 1-1 ◽

Cited By ~ 1

Author(s):

Sunghun Lee ◽

Dong Hun Lee ◽

Bong-Woo Park ◽

Ri Youn Kim ◽

Anh Duc Hoang ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Vascular Regeneration

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Voluntary exercise and cardiac remodeling in a myocardial infarction model

Open Medicine ◽

10.1515/med-2020-0109 ◽

2020 ◽

Vol 15 (1) ◽

pp. 545-555

Author(s):

Hamad Al Shahi ◽

Tomoyasu Kadoguchi ◽

Kazunori Shimada ◽

Kosuke Fukao ◽

Satoshi Matsushita ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Cardiac Remodeling ◽

Skeletal Muscles ◽

Wheel Running ◽

Voluntary Exercise ◽

Fibroblast Growth Factor 21 ◽

Expression Levels ◽

Factor Α ◽

Necrosis Factor

AbstractWe investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.

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Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22020722 ◽

2021 ◽

Vol 22 (2) ◽

pp. 722

Author(s):

Yukino Ogura ◽

Kazuko Tajiri ◽

Nobuyuki Murakoshi ◽

DongZhu Xu ◽

Saori Yonebayashi ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Neutrophil Elastase ◽

Myocardial Injury ◽

Flow Cytometric Analysis ◽

Akt Signaling ◽

Border Zone ◽

Terminal Deoxynucleotidyl Transferase ◽

Deficient Mice

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.

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Endothelial β1 Integrin-Mediated Adaptation to Myocardial Ischemia

Thrombosis and Haemostasis ◽

10.1055/s-0040-1721505 ◽

2021 ◽

Author(s):

Carina Henning ◽

Anna Branopolski ◽

Paula Follert ◽

Oksana Lewandowska ◽

Aysel Ayhan ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Myocardial Ischemia ◽

Cardiac Function ◽

Integrin Subunit ◽

Β1 Integrin ◽

Human Coronary Artery ◽

Tetrazolium Chloride ◽

Magnetic Resonance Imaging Mri ◽

Interfering Rna

Abstract Background Short episodes of myocardial ischemia can protect from myocardial infarction. However, the role of endothelial β1 integrin in these cardioprotective ischemic events is largely unknown. Objective In this study we investigated whether endothelial β1 integrin is required for cardiac adaptation to ischemia and protection from myocardial infarction. Methods Here we introduced transient and permanent left anterior descending artery (LAD) occlusions in mice. We inhibited β1 integrin by intravenous injection of function-blocking antibodies and tamoxifen-induced endothelial cell (EC)-specific deletion of Itgb1. Furthermore, human ITGB1 was silenced in primary human coronary artery ECs using small interfering RNA. We analyzed the numbers of proliferating ECs and arterioles by immunohistochemistry, determined infarct size by magnetic resonance imaging (MRI) and triphenyl tetrazolium chloride staining, and analyzed cardiac function by MRI and echocardiography. Results Transient LAD occlusions were found to increase EC proliferation and arteriole formation in the entire myocardium. These effects required β1 integrin on ECs, except for arteriole formation in the ischemic part of the myocardium. Furthermore, this integrin subunit was also relevant for basal and mechanically induced proliferation of human coronary artery ECs. Notably, β1 integrin was needed for cardioprotection induced by transient LAD occlusions, and the absence of endothelial β1 integrin resulted in impaired growth of blood vessels into the infarcted myocardium and reduced cardiac function after permanent LAD occlusion. Conclusion We showed that endothelial β1 integrin is required for adaptation of the heart to cardiac ischemia and protection from myocardial infarction.

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