Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
Add more filters










Publication year range
1.
Atherosclerosis ; 390: 117450, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38266625

ABSTRACT

BACKGROUND AND AIMS: New treatments are needed to prevent neointimal hyperplasia that contributes to post-angioplasty and stent restenosis in patients with coronary artery disease (CAD) and peripheral arterial disease (PAD). We investigated whether modulating mitochondrial function using mitochondrial division inhibitor-1 (Mdivi-1) could reduce post-vascular injury neointimal hyperplasia by metabolic reprogramming of macrophages from a pro-inflammatory to anti-inflammatory phenotype. METHODS AND RESULTS: In vivo Mdivi-1 treatment of Apoe-/- mice fed a high-fat diet and subjected to carotid-wire injury decreased neointimal hyperplasia by 68%, reduced numbers of plaque vascular smooth muscle cells and pro-inflammatory M1-like macrophages, and decreased plaque inflammation, endothelial activation, and apoptosis, when compared to control. Mdivi-1 treatment of human THP-1 macrophages shifted polarization from a pro-inflammatory M1-like to an anti-inflammatory M2-like phenotype, reduced monocyte chemotaxis and migration to CCL2 and macrophage colony stimulating factor (M-CSF) and decreased secretion of pro-inflammatory mediators. Finally, treatment of pro-inflammatory M1-type-macrophages with Mdivi-1 metabolically reprogrammed them to an anti-inflammatory M2-like phenotype by inhibiting oxidative phosphorylation and attenuating the increase in succinate levels and correcting the decreased levels of arginine and citrulline. CONCLUSIONS: We report that treatment with Mdivi-1 inhibits post-vascular injury neointimal hyperplasia by metabolic reprogramming macrophages towards an anti-inflammatory phenotype thereby highlighting the therapeutic potential of Mdivi-1 for preventing neointimal hyperplasia and restenosis following angioplasty and stenting in CAD and PAD patients.


Subject(s)
Quinazolinones , Vascular System Injuries , Humans , Mice , Animals , Hyperplasia/pathology , Vascular System Injuries/genetics , Metabolic Reprogramming , Cell Movement , Muscle, Smooth, Vascular/pathology , Neointima/metabolism , Anti-Inflammatory Agents/pharmacology , Disease Models, Animal , Cell Proliferation
2.
Basic Res Cardiol ; 118(1): 49, 2023 11 13.
Article in English | MEDLINE | ID: mdl-37955687

ABSTRACT

There remains an unmet need to identify novel therapeutic strategies capable of protecting the myocardium against the detrimental effects of acute ischemia-reperfusion injury (IRI), to reduce myocardial infarct (MI) size and prevent the onset of heart failure (HF) following acute myocardial infarction (AMI). In this regard, perturbations in mitochondrial morphology with an imbalance in mitochondrial fusion and fission can disrupt mitochondrial metabolism, calcium homeostasis, and reactive oxygen species production, factors which are all known to be critical determinants of cardiomyocyte death following acute myocardial IRI. As such, therapeutic approaches directed at preserving the morphology and functionality of mitochondria may provide an important strategy for cardioprotection. In this article, we provide an overview of the alterations in mitochondrial morphology which occur in response to acute myocardial IRI, and highlight the emerging therapeutic strategies for targeting mitochondrial shape to preserve mitochondrial function which have the future therapeutic potential to improve health outcomes in patients presenting with AMI.


Subject(s)
Heart Failure , Myocardial Infarction , Humans , Myocardium , Myocytes, Cardiac , Mitochondria
3.
Autophagy ; 18(9): 2150-2160, 2022 09.
Article in English | MEDLINE | ID: mdl-35012409

ABSTRACT

Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Although caffeine has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), the mechanism underlying this effect is unknown. Here, we demonstrated that caffeine decreased VSMC proliferation and induced macroautophagy/autophagy in an in vivo vascular injury model of restenosis. Furthermore, we studied the effects of caffeine in primary human and mouse aortic VSMCs and immortalized mouse aortic VSMCs. Caffeine decreased cell proliferation, and induced autophagy flux via inhibition of MTOR signaling in these cells. Genetic deletion of the key autophagy gene Atg5, and the Sqstm1/p62 gene encoding a receptor protein, showed that the anti-proliferative effect by caffeine was dependent upon autophagy. Interestingly, caffeine also decreased WNT-signaling and the expression of two WNT target genes, Axin2 and Ccnd1 (cyclin D1). This effect was mediated by autophagic degradation of a key member of the WNT signaling cascade, DVL2, by caffeine to decrease WNT signaling and cell proliferation. SQSTM1/p62, MAP1LC3B-II and DVL2 were also shown to interact with each other, and the overexpression of DVL2 counteracted the inhibition of cell proliferation by caffeine. Taken together, our in vivo and in vitro findings demonstrated that caffeine reduced VSMC proliferation by inhibiting WNT signaling via stimulation of autophagy, thus reducing the vascular restenosis. Our findings suggest that caffeine and other autophagy-inducing drugs may represent novel cardiovascular therapeutic tools to protect against restenosis after angioplasty and/or stent placement.


Subject(s)
Autophagy , Muscle, Smooth, Vascular , Animals , Autophagy/physiology , Caffeine/metabolism , Caffeine/pharmacology , Cell Proliferation , Cells, Cultured , Humans , Mice , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Sequestosome-1 Protein/metabolism , Wnt Signaling Pathway
4.
Cardiovasc Res ; 118(1): 282-294, 2022 01 07.
Article in English | MEDLINE | ID: mdl-33386841

ABSTRACT

AIMS: Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission. METHODS AND RESULTS: Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P<0.001). CONCLUSION: We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine as a novel cardioprotective therapy for improving post-infarction outcomes.


Subject(s)
Dynamins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydralazine/pharmacology , Mitochondria, Heart/drug effects , Mitochondrial Dynamics/drug effects , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/drug effects , Animals , Antioxidants/pharmacology , Apoptosis/drug effects , Disease Models, Animal , Dynamins/metabolism , Female , HeLa Cells , Humans , Isolated Heart Preparation , Male , Mice, Inbred C57BL , Mice, Transgenic , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathology , Myocardial Infarction/enzymology , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/pathology , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Signal Transduction
5.
Sci Rep ; 11(1): 20674, 2021 10 19.
Article in English | MEDLINE | ID: mdl-34667238

ABSTRACT

Vascular restenosis remains a major problem in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Neointimal hyperplasia, defined by post-procedure proliferation and migration of vascular smooth muscle cells (VSMCs) is a key underlying pathology. Here we investigated the role of Interleukin 11 (IL-11) in a mouse model of injury-related plaque development. Apoe-/- mice were fed a hyperlipidaemic diet and subjected to carotid wire injury of the right carotid. Mice were injected with an anti-IL11 antibody (X203), IgG control antibody or buffer. We performed ultrasound analysis to assess vessel wall thickness and blood velocity. Using histology and immunofluorescence approaches, we determined the effects of IL-11 inhibition on VSMC and macrophages phenotypes and fibrosis. Treatment of mice with carotid wire injury using X203 significantly reduced post-endothelial injury vessel wall thickness, and injury-related plaque, when compared to control. Immunofluorescence staining of the injury-related plaque showed that X203 treatment did not reduce macrophage numbers, but reduced the number of VSMCs and lowered matrix metalloproteinase 2 (MMP2) levels and collagen content in comparison to control. X203 treatment was associated with a significant increase in smooth muscle protein 22α (SM22α) positive cells in injury-related plaque compared to control, suggesting preservation of the contractile VSMC phenotype. Interestingly, X203 also reduced the collagen content of uninjured carotid arteries as compared to IgG, showing an additional effect on hyperlipidemia-induced arterial remodeling in the absence of mechanical injury. Therapeutic inhibition of IL-11 reduced vessel wall thickness, attenuated neointimal hyperplasia, and has favorable effects on vascular remodeling following wire-induced endothelial injury. This suggests IL-11 inhibition as a potential novel therapeutic approach to reduce arterial stenosis following revascularization in CAD and PAD patients.


Subject(s)
Antibodies, Neutralizing/pharmacology , Carotid Arteries/drug effects , Carotid Artery Injuries/drug therapy , Hyperplasia/drug therapy , Interleukin-11/metabolism , Animals , Carotid Arteries/metabolism , Carotid Artery Injuries/metabolism , Cell Movement/drug effects , Cell Proliferation/drug effects , Collagen/metabolism , Disease Models, Animal , Hyperplasia/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Matrix Metalloproteinase 2/metabolism , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Neointima/drug therapy , Neointima/metabolism , Vascular Remodeling/drug effects
6.
EBioMedicine ; 57: 102884, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32653860

ABSTRACT

Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such, new treatments are needed to protect the myocardium against the damaging effects of the acute ischaemia and reperfusion injury (IRI) that occurs in AMI, in order to reduce myocardial infarct (MI) size, preserve cardiac function, and improve patient outcomes. In this regard, cardiac mitochondria play a dual role as arbiters of cell survival and death following AMI. Therefore, preventing mitochondrial dysfunction induced by acute myocardial IRI is an important therapeutic strategy for cardioprotection. In this article, we review the role of mitochondria as key determinants of acute myocardial IRI, and we highlight their roles as therapeutic targets for reducing MI size and preventing HF following AMI. In addition, we discuss the challenges in translating mitoprotective strategies into the clinical setting for improving outcomes in AMI patients.


Subject(s)
Cardiotonic Agents/therapeutic use , Heart Failure/genetics , Mitochondria/genetics , Myocardial Infarction/genetics , Heart Failure/drug therapy , Heart Failure/pathology , Humans , Mitochondria/drug effects , Mitochondria/pathology , Molecular Targeted Therapy , Myocardial Infarction/drug therapy , Myocardial Infarction/pathology , Myocardium/metabolism , Myocardium/pathology , Reperfusion Injury/drug therapy , Reperfusion Injury/genetics , Reperfusion Injury/pathology
7.
Thromb Haemost ; 120(4): 658-670, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32131129

ABSTRACT

Despite strong evidence supporting the cellular interplay between haemostasis and innate immunity, humoral connections between blood coagulation and the behavior of inflammatory macrophages are not well understood. In this study, we investigated changes in gene expression of selected cytokines and chemokines and their secretion profiles following thrombin stimulation of murine macrophages. Thrombin promoted differentiation of macrophages into an M1-like phenotype that was associated with the expression of classical pro-inflammatory markers. The cellular actions of thrombin on macrophages were mediated in part by protease-activated receptor-1 (PAR-1) and were dependent on phosphoinositide 3-kinase/AKT and nuclear factor-κB. Moreover, heat-denatured thrombin stimulated the secretion of some pro-inflammatory mediators to the same magnitude indicating that different receptors transmit cellular signals of enzymatically active thrombin and nonactive thrombin, the latter remaining so far undefined. Finally, pretreatment of macrophages with thrombin resulted in tolerance against secondary stimulation by lipopolysaccharide with regard to expression of tumor necrosis factor-α. These results provide new insights into the molecular link between the key enzyme of haemostasis and innate immunity responses.


Subject(s)
Inflammation/metabolism , Macrophages/metabolism , Thrombin/metabolism , Animals , Cell Differentiation , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Regulation , Humans , Inflammation/pathology , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/metabolism , Oncogene Protein v-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Receptor, PAR-1/genetics , Th1 Cells/immunology , Thrombin/immunology
8.
Cond Med ; 3(4): 227-238, 2020 Aug.
Article in English | MEDLINE | ID: mdl-34296067

ABSTRACT

New treatments are urgently needed to reduce myocardial infarct size and prevent adverse post-infarct left ventricular remodeling, in order to preserve cardiac function, and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI). In this regard, extracellular vesicles (EVs) have emerged as key mediators of cardioprotection. Endogenously produced EVs are known to play crucial roles in maintaining normal cardiac homeostasis and function, by acting as mediators of intercellular communication between different types of cardiac cells. Endogenous EVs have also been shown to contribute to innate cardioprotective strategies such as remote ischemic conditioning. In terms of EV-based therapeutics, stem cell-derived EVs have been shown to confer cardioprotection in a large number of small and large animal AMI models, and have the therapeutic potential to be applied in the clinical setting for the benefit of AMI patients, although several challenges need to be overcome. Finally, EVs may be used as vehicles to deliver therapeutics to the infarcted heart, providing a potential synergist approach to cardioprotection. In this review article, we highlight the various roles that EVs play as mediators and deliverers of cardioprotection, and discuss their therapeutic potential for improving clinical outcomes following AMI.

9.
Int J Mol Sci ; 20(16)2019 Aug 15.
Article in English | MEDLINE | ID: mdl-31443187

ABSTRACT

Background: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods: Adult pigs (30-40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.


Subject(s)
Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/metabolism , Quinazolinones/therapeutic use , Animals , Disease Models, Animal , Echocardiography , Female , Mitochondrial Dynamics/drug effects , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Pilot Projects , Swine , Ventricular Function, Left/drug effects
10.
Arterioscler Thromb Vasc Biol ; 39(3): 387-401, 2019 03.
Article in English | MEDLINE | ID: mdl-30651003

ABSTRACT

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr-/- mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe-/- mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.


Subject(s)
Atherosclerosis/prevention & control , Furin/antagonists & inhibitors , Plaque, Atherosclerotic/drug therapy , alpha 1-Antitrypsin/therapeutic use , Animals , Aorta/enzymology , Atherosclerosis/genetics , Atherosclerosis/pathology , Carotid Artery, Common , Disease Progression , Drug Evaluation, Preclinical , Enzyme Induction/drug effects , Furin/genetics , Furin/physiology , Gene Expression Regulation/drug effects , Macrophages/physiology , Male , Matrix Metalloproteinase 2/analysis , Mice , Mice, Inbred C57BL , Monocytes/physiology , Plaque, Atherosclerotic/pathology , Receptors, LDL/deficiency , Tunica Intima/drug effects , Tunica Intima/pathology , Vascular Remodeling , alpha 1-Antitrypsin/pharmacology
11.
Cond Med ; 1(5): 239-246, 2018 Aug.
Article in English | MEDLINE | ID: mdl-30338314

ABSTRACT

Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such novel therapies are needed to reduce myocardial infarct (MI) size, and preserve left ventricular (LV) systolic function in order to reduce the propensity for HF following AMI. Mitochondria are dynamic organelles that can undergo morphological changes by two opposing processes, mitochondrial fusion and fission. Changes in mitochondrial morphology and turnover are a vital part of maintaining mitochondrial health, DNA stability, energy production, calcium homeostasis, cellular division, and differentiation, and disturbances in the balance of fusion and fission can predispose to mitochondrial dysfunction and cell death. Changes in mitochondrial morphology are governed by mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1) and mitochondrial fission proteins (Drp1, hFis1, and Mff). Recent experimental data suggest that mitochondria undergo fission during acute ischemia/reperfusion injury (IRI), generating fragmented dysfunctional mitochondrial and predisposing to cell death. We and others have shown that genetic and pharmacological inhibition of the mitochondrial fission protein Drp1 can protect cardiomyocytes from acute IRI and reduce MI size. Novel components of the mitochondrial fission machinery, mitochondrial dynamics proteins of 49 kDa (MiD49) and mitochondrial dynamics proteins of 51 kDa (MiD51), have been recently described, which have been shown to mediating mitochondrial fission by targeting Drp1 to the mitochondrial surface. In this review article, we provide an overview of MiD49 and MiD51, and highlight their potential as novel therapeutic targets for treating cardiovascular diseases such as AMI, anthracycline cardiomyopathy, and pulmonary arterial hypertension.

12.
Cond Med ; 1(5): 247-258, 2018 Aug.
Article in English | MEDLINE | ID: mdl-30338315

ABSTRACT

One of the primary therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial infarct size and optimizing cardiac function following acute myocardial infarction (AMI). Patients with AMI who underwent reperfusion therapy display dysfunction of the coronary endothelium. Consequently, ischemic endothelial cells become more permeable and weaken their natural anti-thrombotic and anti-inflammatory potential. Ischemia-reperfusion injury (IRI) is associated with activation of the humoral and cellular components of the hemostatic and innate immune system, and also with excessive production of reactive oxygen species (ROS), the inhibition of nitric oxide synthase, and with inflammatory processes. Given its essential role in the regulation of vascular homeostasis, involving platelets and leukocytes among others, dysfunctional endothelium can lead to increased risk of coronary vasospasm and thrombosis. Endothelial dysfunction can be prevented by ischemic conditioning with a protective intervention based on limited intermittent periods of ischemia and reperfusion. The molecular mechanisms and signal transduction pathways underlying conditioning phenomena in the coronary endothelium have been described as involving less ROS production, reduced adhesion of neutrophils to endothelial cells and diminished inflammatory reactions. This review summarizes our current understanding of the cellular and molecular mechanisms regulating IRI-affected and -damaged coronary endothelium, and how ischemic conditioning may preserve its function.

13.
Arch Med Res ; 49(8): 522-529, 2018 11.
Article in English | MEDLINE | ID: mdl-30213474

ABSTRACT

The presence of different APOE isoforms represents a well-known risk factor for cardiovascular diseases. Besides the pleiotropic effects of APOE polymorphism on heart and neurological diseases, this review summarizes the less-known functions of APOE and the possible implications for cardiovascular disorders. Beyond the role as lipid transporting protein, its involvement in lipid membrane homeostasis and signaling, as well as its nuclear transcriptional effects suggests a more complex role of APOE, receiving great interest from researchers and physicians from all medical fields. Due to the presence of different APOE isoforms in human population, understanding APOE's role in pathological processes represents not only a challenge, but a demand for further development of therapeutic strategies for cardiovascular diseases.


Subject(s)
Apolipoproteins E/metabolism , Biological Transport/physiology , Cardiovascular Diseases/pathology , Carrier Proteins/metabolism , Lipid Metabolism/physiology , Humans , Lipids , Nervous System Diseases , Polymorphism, Genetic , Protein Isoforms/metabolism , Risk Factors
14.
Pharmacol Ther ; 186: 73-87, 2018 06.
Article in English | MEDLINE | ID: mdl-29330085

ABSTRACT

Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI. In this article, we provide an overview of the multiple players (and their dynamic roles) involved in the complex inflammatory response to AMI and subsequent LV remodeling, and highlight future opportunities for targeting inflammation as a therapeutic strategy for limiting MI size, preventing adverse LV remodeling, and reducing heart failure in AMI patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Heart Failure/prevention & control , Inflammation Mediators/metabolism , Myocardial Infarction/drug therapy , Ventricular Remodeling/drug effects , Animals , Anti-Inflammatory Agents/administration & dosage , Disease Models, Animal , Heart Failure/immunology , Humans , Inflammation , Myocardial Infarction/immunology , Ventricular Remodeling/immunology
SELECTION OF CITATIONS
SEARCH DETAIL
...