scholarly journals Mitochondrial Fusion Protein Mfn2 and Its Role in Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Lei Chen ◽  
Bilin Liu ◽  
Yuan Qin ◽  
Anqi Li ◽  
Meng Gao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Quality Control ◽  
Mitofusin 2 ◽  
Multifunctional Protein ◽  
Pathological Conditions ◽  
And Function

Mitofusin 2 (Mfn2) is a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial network regulation. It is an essential multifunctional protein that participates in various biological processes under physical and pathological conditions, including mitochondrial fusion, reticulum–mitochondria contacts, mitochondrial quality control, and apoptosis. Mfn2 dysfunctions have been found to contribute to cardiovascular diseases, such as ischemia-reperfusion injury, heart failure, and dilated cardiomyopathy. Here, this review mainly focuses on what is known about the structure and function of Mfn2 and its crucial role in heart failure.

scholarly journals The Role of 5-Lipoxygenase and Leukotrienes in Shock and Ischemia-Reperfusion Injury

2007 ◽  
Vol 7 ◽  
pp. 56-74 ◽  
Author(s):  
Antonietta Rossi ◽  
Carlo Pergola ◽  
Salvatore Cuzzocrea ◽  
Lidia Sautebin
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Biological Activities ◽  
Ischemia Reperfusion ◽  
Targeted Disruption ◽  
Pathological Conditions ◽  
Metabolic Products ◽  
Important Regulator ◽  
Multicellular Organisms

The leukotrienes (LTs) are metabolic products of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. The biological activities of LTs suggest that they are mediators of acute inflammatory and immediate hypersensitivity responses. In particular, the 5-LO activation has been proposed to be an important regulator for pathogenesis in multicellular organisms. The role of LTs in tissue damage, associated with septic and nonseptic shock and ischemia-reperfusion, has been extensively studied by the use of 5-LO inhibitors, receptor antagonists, and mice with a targeted disruption of the 5-LO gene (5-LOKO). In particular, several data indicate that LTs regulate neutrophil trafficking in damaged tissue in shock and ischemia-reperfusion, mainly through the modulation of adhesion molecule expression. This concept may provide new insights into the interpretation of the protective effect of 5-LO inhibition, which may be useful in the therapy of pathological conditions associated with septic and nonseptic shock and ischemia-reperfusion injury.

Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michelle L Nieman ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
G Protein ◽  
Knockout Mice ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

Abstract 14834: Protective Role of Cardiomyocyte-derived Ddt in Ischemic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yina Ma ◽  
Xiaoyue Hu ◽  
Daniel Pfau ◽  
Xiaohong Wu ◽  
Veena Rao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Map Kinase ◽  
Ischemic Cardiomyopathy ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
P38 Map Kinase ◽  
Lv Function ◽  
Acute Ischemia ◽  
S6 Kinase ◽  
Sham Surgery

Background: D-dopachrome tautomerase (DDT), the only homolog of macrophage migration inhibitory factor (MIF), is a cytokine highly expressed in cardiomyocytes and exerts autocrine-paracrine effects by signaling through the CD74 receptor. Endogenous DDT and MIF prevent acute ischemia-reperfusion injury and pressure overload-induced heart failure in mice. This study investigated whether endogenous cardiomyocyte DDT has a role in ischemic cardiomyopathy (ICM). Methods: LV tissue was obtained from patients with ICM during heart transplantation and from non-transplanted donor hearts. Plasma DDT concentrations were measured in heart failure outpatients with ICM. Cardiomyocyte-specific DDT knockout (cKO) and littermate control (CON) mice underwent MI or sham surgery. Serial echocardiography was performed to assess LV remodeling after MI or sham surgery. Tissue from the non-infarct region was analyzed 3 days and 4 weeks after MI or sham surgery for histology and molecular studies. Results: Cardiac DDT mRNA and protein expression were reduced in LV from patients transplanted for ICM (n=8). Plasma DDT concentrations below the median value were associated with worse survival in ICM outpatients (p<0.05, n=32). In mice, baseline LV function was similar in DDT cKO and CON after sham surgery and 3 days post-MI. However, DDT cKO mice developed more rapid LV dilatation and decreased LV ejection fraction and stroke volume as early as 1-week post-MI (n=4-6/group, all P<0.05). The DDT cKO mice had smaller cardiomyocyte cross-sectional area 4 weeks after MI (p <0.05), as well as early diminished phosphorylation of mTOR and S6-kinase (3 days post-MI). They also showed increased apoptosis 3 days post-MI and an early increase in p38 MAP kinase activation. Conclusion: Cardiomyocyte-derived DDT prevents adverse cardiac remodeling in ICM, potentially through modulating mTOR/S6 kinase (adaptive hypertrophy) and p38 MAP kinase (limiting apoptosis). Down-regulation of DDT in patients with ICM may contribute to the pathogenesis of advanced heart failure.

scholarly journals Histone Hyperacetylation as a Response to Global Brain Ischemia Associated with Hyperhomocysteinemia in Rats

2018 ◽  
Vol 19 (10) ◽  
pp. 3147 ◽  
Author(s):  
Barbara Tóthová ◽  
Mária Kovalská ◽  
Dagmar Kalenská ◽  
Anna Tomašcová ◽  
Ján Lehotský
Keyword(s):  
Histone Acetylation ◽  
Primary Motor Cortex ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cresyl Violet ◽  
Cortical Region ◽  
Global Brain Ischemia ◽  
Endogenous Factors ◽  
Pathological Conditions ◽  
Cornu Ammonis

Epigenetic regulations play an important role in both normal and pathological conditions of an organism, and are influenced by various exogenous and endogenous factors. Hyperhomocysteinemia (hHcy), as a risk factor for several pathological conditions affecting the central nervous system, is supposed to alter the epigenetic signature of the given tissue, which therefore worsens the subsequent damage. To investigate the effect of hHcy in combination with ischemia-reperfusion injury (IRI) and histone acetylation, we used the hHcy animal model of global forebrain ischemia in rats. Cresyl violet staining showed massive neural disintegration in the M1 (primary motor cortex) region as well as in the CA1 (cornu ammonis 1) area of the hippocampus induced by IRI. Neural loss was significantly higher in the group with induced hHcy. Moreover, immunohistochemistry and Western blot analysis of the brain cortex showed prominent changes in the acetylation of histones H3 and H4, at lysine 9 and 12, respectively, as a result of IRI and induced hHcy. It seems that the differences in histone acetylation patterns in the cortical region have a preferred role in pathological processes induced by IRI associated with hHcy and could be considered in therapeutic strategies.

scholarly journals Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2884 ◽  
Author(s):  
Eun-Jung In ◽  
Yuno Lee ◽  
Sushruta Koppula ◽  
Tae-Yeon Kim ◽  
Jun-Hyuk Han ◽  
...  
Keyword(s):  
Cell Death ◽  
Md Simulation ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Direct Interaction ◽  
Inhibitory Effect ◽  
Therapeutic Implications ◽  
Pathological Conditions ◽  
Tnf Α

Necroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none of them are currently in clinical use. In the present study, we identified a new compound, 4-({[5-(4-aminophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-N-(1,3-thiazol-2-yl) benzamide (NTB451), with significant inhibitory activity on the necroptosis induced by various triggers, such as tumor necrosis factor-α (TNF-α) and toll-like receptor (TLR) agonists. Mechanistic studies revealed that NTB451 inhibited phosphorylation and oligomerization of mixed lineage kinase domain like (MLKL), and this activity was linked to its inhibitory effect on the formation of the receptor interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3 complex. Small interfering RNA (siRNA)-mediated RIPK1 knockdown, drug affinity responsive target stability assay, and molecular dynamics (MD) simulation study illustrated that RIPK1 is a specific target of NTB451. Moreover, MD simulation showed a direct interaction of NTB451 and RIPK1. Further experiments to ensure that the inhibitory effect of NTB451 was restricted to necroptosis and NTB451 had no effect on nuclear factor-κB (NF-κB) activation or apoptotic cell death upon triggering with TNF-α were also performed. Considering the data obtained, our study confirmed the potential of NTB451 as a new necroptosis inhibitor, suggesting its therapeutic implications for pathological conditions induced by necroptotic cell death.

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