scholarly journals Correlation Between Vascular Inflammation Markers, Diastolic Dysfunction and Cardiovascular Risk in Patients with Takayasu Arteritis

2021 ◽  
Author(s):  
Sebastiano Cicco ◽  
Vanessa Desantis ◽  
Antonio Vacca ◽  
Gerardo Cazzato ◽  
Antonio Giovanni Solimando ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Takayasu Arteritis ◽  
Th17 Cells ◽  
Vessel Wall ◽  
Immune Cell ◽  
Vascular Inflammation ◽  
Atherosclerotic Cardiovascular Disease ◽  
Infliximab Treatment ◽  
Increased Risk

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Hypertension and atherosclerosis lead to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched hypertensive and atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical evaluation of the vessel wall was performed to compare the in vivo results. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. These data have been associated with uric acid levels. A significant increase in aortic stiffness was also noted and associated with peripheral T lymphocyte levels. CD3+CD4+ cell infiltrates were detected in the vessel wall samples of these patients. They had a lower mean percentage of Tregs at T0 than controls, but levels increased significantly at T18. Opposite results were found in Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms of vessel damage, including atherosclerosis, underlie TAK patients compared with control subjects. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.

scholarly journals AB0473 “HALO SIGN” IN ULTRASOUND OF TEMPORAL, FACIAL AND AXILLARY ARTERIES: ASSOCIATIONS WITH CLINICAL SYMPTOMATOLOGY AND LABORATORY FINDINGS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1534.2-1535
Author(s):  
G. Evangelatos ◽  
G. E. Fragoulis ◽  
A. Iliopoulos
Keyword(s):  
Vessel Wall ◽  
Vascular Inflammation ◽  
Inflammation Markers ◽  
Laboratory Findings ◽  
Clinical Symptomatology ◽  
Temporal Arteries ◽  
Halo Sign ◽  
Increased Risk ◽  
Us Findings ◽  
Specific Symptoms

Background:Giant cell arteritis (GCA) has two subtypes, the cranial form (“cranial GCA”) and the large-vessel form (“LV-GCA”). GCA can present with “cranial” symptoms (headache, visual symptoms, jaw claudication, scalp tenderness), constitutional symptoms (fever, fatigue), limb claudication and symptoms of polymyalgia rheumatica (PMR) and usually causes increased inflammation markers, anemia and thrombocytosis. Ultrasound (US) of the temporal and axillary arteries has a well-established role in cranial GCA and LV-GCA diagnosis, respectively. However, it is unknown whether specific clinical and laboratory parameters are linked with US findings suggestive of vascular inflammation (“halo” sign).Objectives:The aim of this study was to examine possible association between clinical and laboratory characteristics of the patients and detection of vessel wall inflammation in the US.Methods:Patients ≥50 years old with elevated ESR (≥50mm/h) and/or CRP (≥10mg/L) that presented in our outpatient rheumatology clinics from July 2017 to December 2019 with possible clinical diagnosis of GCA were included. Three groups were compared: Patients with “cranial symptoms” (with or without PMR), patients with PMR symptoms only and patients with increased inflammation markers without specific symptoms indicative of GCA. Temporal arteries and their main branches, as well as facial and axillary arteries were evaluated by US bilaterally for the presence of non-compressible “halo sign” at the vessel wall. Clinical symptomatology and the occurrence of anemia and thrombocytosis were recorded.Results:52 patients were included. 71.2% were females, with a mean±SD age of 71.0±10.0 years. 17 patients had “cranial symptoms” (seven patients with concomitant PMR and ten without), 17 patients had PMR symptoms only, while 18 patients had non-specific symptoms (e.g. fever) (Table 1). Among 17 patients with “cranial symptoms”, 7/7 (100%) with concomitant PMR had a positive temporal US, while only 3 out of 10 (30%) without PMR had a positive temporal US (p<0.01) and US was indeterminate in 2 of them (20%). Collectively, 10/17 (58.8%) of patients with “cranial symptoms” and systemic inflammation had a US examination compatible with GCA. No patient with “cranial symptoms” had a positive US of axillary arteries. No patient with only PMR symptoms, had “halo sign” in temporal and facial arteries, while 3 out of 17 (17.6%) had a positive axillary US. From the 18 patients with elevated ESR/CRP, one had a positive temporal US and another one had a positive axillary US. Regarding specific symptoms, positive temporal US was associated with new headache (p=0.003), vision impairment (p=0.001), jaw claudication (p=0.05), scalp tenderness (p=0.01) and fever (P=0.002), but not with PMR (p=0.317). Thrombocytosis was associated with an increased risk for “halo sign” detection in temporal (p=0.04) and facial (p=0.007) arteries, but not in axilliary arteries (p=0.52).Conclusion:60% of patients with “cranial symptoms” and elevated inflammation markers have US temporal findings indicative of GCA. This is more pronounced in patients with concomitant PMR symptoms and is associated with specific symptomatology. 18% of patients with only PMR symptoms might have LV-GCA, while those with high ESR/CRP without GCA-related symptoms rarely have “halo sign” in US.Disclosure of Interests:None declared

scholarly journals Crocetin Inhibits Lipopolysaccharide-Induced Inflammatory Response in Human Umbilical Vein Endothelial Cells

2016 ◽  
Vol 40 (3-4) ◽  
pp. 443-452 ◽  
Author(s):  
Lei Song ◽  
Chen Kang ◽  
Yuan Sun ◽  
Wenrui Huang ◽  
Wei Liu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Cell ◽  
Umbilical Vein ◽  
Vascular Inflammation ◽  
Bioactive Compound ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells ◽  
Natural Herb

Background/Aim: Crocetin is a readily bioavailable and bioactive compound extracted from Saffron. Previous studies indicated its various biomedical properties including antioxidant and anti-coagulation potencies. However, its effect on inflammation, notably within the cardiovascular system, has not been investigated yet. In the present study, we utilized human umbilical vein endothelial cell (HUVEC) to elucidate the effect of Crocetin on vascular inflammation. Methods: Cell viability and toxicity were evaluated by MTT and Lactate dehydrogenase (LDH) assay, respectively. Pro-inflammatory chemokine <under>M</under>onocyte Chemoattractant <under>P</under>rotein-1 (MCP-1) and <under>I</under>nter<under>l</under>eukin-8 (IL-8) expressions were determined by RT-PCR and ELISA. With fluorescence labeled U937 cells, we examined immune cell adhesion to the inflamed HUVEC in vitro, which was further confirmed by the H&amp;E staining in the murine subcutaneous endothelium in vivo. Results: Upon Lipopolysaccharide (LPS)-induced inflammatory response in HUVECs, Crocetin ameliorated cell cytotoxicity, suppressed MCP-1 and IL-8 expressions through blocking NF-κB p65 signaling transduction. Moreover, Crocetin inhibited immune cells adhesion and infiltration to inflamed endothelium, which is a key step in inflammatory vascular injury. Conclusions: These findings suggest that Crocetin, a natural herb extract, is a potent suppressor of vascular endothelial inflammation.

scholarly journals Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
T. G. Mastenbroek ◽  
M. F. A. Karel ◽  
M. Nagy ◽  
W. Chayoua ◽  
E. I. J. Korsten ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
Positive Trend ◽  
Atherosclerotic Cardiovascular Disease ◽  
Protective Effects ◽  
Endothelial Denudation ◽  
Vascular Stiffening

Abstract While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation and vascular remodelling upon vascular damage. The aim of this study was to examine the effects of aspirin and/or rivaroxaban on injury-induced murine arterial thrombus formation in vivo and in vitro, vessel-wall remodelling, and platelet-leukocyte aggregates. Temporary ligation of the carotid artery of C57BL/6 mice, fed a western type diet, led to endothelial denudation and sub-occlusive thrombus formation. At the site of ligation, the vessel wall stiffened and the intima-media thickened. Aspirin treatment antagonized vascular stiffening and rivaroxaban treatment led to a positive trend towards reduced stiffening. Local intima-media thickening was antagonized by both aspirin or rivaroxaban treatment. Platelet-leukocyte aggregates and the number of platelets per leukocyte were reduced in aspirin and/or rivaroxaban treatment groups. Furthermore, rivaroxaban restricted thrombus growth and height in vitro. In sum, this study shows vascular protective effects of aspirin and rivaroxaban, upon vascular injury of the mouse artery.

scholarly journals Dipeptidyl Peptidase 4: A New Link between Diabetes Mellitus and Atherosclerosis?

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Wellington Santana da Silva Júnior ◽  
Amélio Fernando de Godoy-Matos ◽  
Luiz Guilherme Kraemer-Aguiar
Keyword(s):  
Diabetes Mellitus ◽  
Vascular Function ◽  
Dipeptidyl Peptidase ◽  
Noncommunicable Diseases ◽  
Atherosclerotic Cardiovascular Disease ◽  
Dipeptidyl Peptidase 4 ◽  
Increased Risk ◽  
Increase Insulin Secretion

Type 2 diabetes mellitus (T2DM) has become one of the most prevalent noncommunicable diseases in the past years. It is undoubtedly associated with atherosclerosis and increased risk for cardiovascular diseases. Incretins, which are intestinal peptides secreted during digestion, are able to increase insulin secretion and its impaired function and/or secretion is involved in the pathophysiology of T2DM. Dipeptidyl peptidase 4 (DPP4) is an ubiquitous enzyme that regulates incretins and consequently is related to the pathophysiology of T2DM. DPP4 is mainly secreted by endothelial cells and acts as a regulatory protease for cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. In T2DM, the activity of DPP4 seems to be increased and there are a growing number ofin vitroandin vivostudies suggesting that this enzyme could be a new link between T2DM and atherosclerosis. Gliptins are a new class of pharmaceutical agents that acts by inhibiting DPP4. Thus, it is expected that gliptin represents a new pharmacological approach not only for reducing glycemic levels in T2DM, but also for the prevention and treatment of atherosclerotic cardiovascular disease in diabetic subjects. We aimed to review the evidences that reinforce the associations between DPP4, atherosclerosis, and T2DM.

scholarly journals Hyperaldosteronism induces left atrial systolic and diastolic dysfunction

2016 ◽  
Vol 311 (4) ◽  
pp. H1014-H1023 ◽  
Author(s):  
Jan-Christian Reil ◽  
Marcus Tauchnitz ◽  
Qinghai Tian ◽  
Mathias Hohl ◽  
Dominik Linz ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Diastolic Dysfunction ◽  
Left Atrial ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Volume Analysis ◽  
Atrial Size ◽  
Increased Risk ◽  
Diastolic Left Ventricular Dysfunction

Patients with hypertension and hyperaldosteronism show an increased risk of stroke compared with patients with essential hypertension. Aim of the study was to assess the effects of aldosterone on left atrial function in rats as a potential contributor to thromboembolism. Osmotic mini-pumps delivering 1.5 μg aldosterone/h were implanted in rats subcutaneously (Aldo, n = 39; controls, n = 38). After 8 wk, left ventricular pressure-volume analysis of isolated working hearts was performed, and left atrial systolic and diastolic function was also assessed by atrial pressure-diameter loops. Moreover, left atrial myocytes were isolated to investigate their global and local Ca2+ handling and contractility. At similar heart rates, pressure-volume analysis of isolated hearts and in vivo hemodynamic measurements revealed neither systolic nor diastolic left ventricular dysfunction in Aldo. In particular, atrial filling pressures and atrial size were not increased in Aldo. Aldo rats showed a significant reduction of atrial late diastolic A wave, atrial active work index, and increased V waves. Consistently, in Aldo rats, sarcomere shortening and the amplitude of electrically evoked global Ca2+ transients were substantially reduced. Sarcoplasmic reticulum-Ca2+ content and fractional Ca2+ release were decreased, substantiated by a reduced sarcoplasmic reticulum calcium ATPase activity, resulting from a reduced CAMKII-evoked phosphorylation of phospholamban. Hyperaldosteronism induced atrial systolic and diastolic dysfunction, while atrial size and left ventricular hemodynamics, including filling pressures, were unaffected in rats. The described model suggests a direct causal link between hyperaldosteronism and decreased atrial contractility and diastolic compliance.

scholarly journals ISG20L2 as a Novel Prognostic Biomarker Facilitates the Progression of Pancreatic Cancer via Glycolysis

2021 ◽  
Author(s):  
Jianming Wei ◽  
Xibo Gao ◽  
Bingbing Ren ◽  
Daqing Sun ◽  
Tong Liu
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Xenograft Model ◽  
Gene Set Enrichment Analysis ◽  
Pathway Gene ◽  
Increased Risk ◽  
And Migration ◽  
Vesicle Cycle

Abstract Background: Longstanding type 2 diabetes mellitus (T2DM) is an increased risk of pancreatic cancer (PC) in western populations, and PC is also a cause of T2DM. However, the association of glucose metabolism between T2DM and PC remains unclear. Methods: Differentially expressed genes (DEGs) were identified by bioinformatic analysis from Gene Expression Omnibus (GEO) datasets GSE20966 and GSE16515, respectively. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Set Enrichment Analysis (GSEA), the Kaplan-Meier (KM) Plotter and Tumor Immune Estimation Resource (TIMER) database were applied. Pancreatic cancer cell lines and primary PDAC samples were used. Cell culture, immunohistochemistry (IHC), siRNA transfection, Western blot, RT-PCR, and migration assay, animal xenograft model studies and statistical analysis were performed in this study. Results: We identified 64 DEGs in GSE20966 of T2DM, and 296 DEGs were identified in GSE16515 of pancreatic cancer, respectively. T2DM-DEGs were mainly enriched in synaptic vesicle cycle, protein export. KEGG pathways in pancreatic cancer included spliceosome, RNA transport. Here, ISG20L2 was identified as only a co-expressed gene between T2DM and PDAC. We found that the expression of ISG20L2 was associated with tumor immune cell infiltration. ISG20L2 was significantly upregulated in PDAC and associated with prognosis of PDAC patients. Moreover, ISG20L2 expression was regulated by GLUT1, HK2, LDHA, PKM1 and PKM2 related with glycolysis in PDAC. ISG20L2 promoted PDAC cell proliferation and migration both in vitro and in vivo. Conclusion: This study showed that ISG20L2 promoted the progression and ISG20L2 may be a potential therapeutic strategy in PDAC.

scholarly journals ISG20L2 as a Novel Prognostic Biomarker Facilitates the Progression of Pancreatic Cancer Via Glycolysis

2021 ◽  
Author(s):  
Jianming Wei ◽  
Xibo Gao ◽  
Bingbing Ren ◽  
Daqing Sun ◽  
Tong Liu
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Xenograft Model ◽  
Gene Set Enrichment Analysis ◽  
Pathway Gene ◽  
Increased Risk ◽  
And Migration ◽  
Vesicle Cycle

Abstract Background: Longstanding type 2 diabetes mellitus (T2DM) is an increased risk of pancreatic cancer (PC) in western populations, and PC is also a cause of T2DM. However, the association of glucose metabolism between T2DM and PC remains unclear. Methods: Differentially expressed genes (DEGs) were identified by bioinformatic analysis from Gene Expression Omnibus (GEO) datasets GSE20966 and GSE16515, respectively. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Set Enrichment Analysis (GSEA), the Kaplan-Meier (KM) Plotter and Tumor Immune Estimation Resource (TIMER) database were applied. Pancreatic cancer cell lines and primary PDAC samples were used. Cell culture, immunohistochemistry (IHC), siRNA transfection, Western blot, RT-PCR, and migration assay, animal xenograft model studies and statistical analysis were performed in this study. Results: We identified 64 DEGs in GSE20966 of T2DM, and 296 DEGs were identified in GSE16515 of pancreatic cancer, respectively. T2DM-DEGs were mainly enriched in synaptic vesicle cycle, protein export. KEGG pathways in pancreatic cancer included spliceosome, RNA transport. Here, ISG20L2 was identified as only a co-expressed gene between T2DM and PDAC. We found that the expression of ISG20L2 was associated with tumor immune cell infiltration. ISG20L2 was significantly upregulated in PDAC and associated with prognosis of PDAC patients. Moreover, ISG20L2 expression was regulated by GLUT1 , HK2 , LDHA , PKM1 and PKM2 related with glycolysis in PDAC. ISG20L2 promoted PDAC cell proliferation and migration both in vitro and in vivo. Conclusion: This study showed that ISG20L2 promoted the progression and ISG20L2 may be a potential therapeutic strategy in PDAC.

scholarly journals A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells

2021 ◽  
Author(s):  
Seon-Yeong Lee ◽  
Su-Jin Moon ◽  
Young-Mee Moon ◽  
Hyeon-Beom Seo ◽  
Jun-Geol Ryu ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Immune Cell ◽  
Joint Damage ◽  
Treg Cells ◽  
Osteoclast Formation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Anti Inflammatory

Abstract Objective The interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two β-subunits (p40 and EBI3). However, a β-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1. Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation. Methods The presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA. Results Clinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1β, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+ (regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner. Conclusion In this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.

scholarly journals β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke

2021 ◽  
pp. 0271678X2098455
Author(s):  
Claudia Grossi ◽  
Carolina Artusi ◽  
PierLuigi Meroni ◽  
Maria Orietta Borghi ◽  
Laura Neglia ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Vascular Inflammation ◽  
Annexin V ◽  
Artery Occlusion ◽  
Brain Parenchyma ◽  
Glycoprotein I ◽  
Increased Risk ◽  
Cerebral Artery Occlusion

Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.

scholarly journals Hypoglycemia Induced Mitochondrial Connexin-43 Accumulation Aggravates Diabetic Cardiomyopathy

2021 ◽  
Author(s):  
Xing Wei ◽  
Andrew Chia Hao Chang ◽  
Haishuang Chang ◽  
Shan Xu ◽  
Yilin Xue ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Murine Model ◽  
Connexin 43 ◽  
Calcium Handling ◽  
Glucose Fluctuation ◽  
Increased Risk

Abstract Background: Diabetic cardiomyopathy (DCM) is a complex multifaceted disease responsible for elevated hospitalization and mortality in patients with diabetes mellitus (DM). DCM patients exhibit subclinical diastolic dysfunction, progression towards systolic impairment, and abnormal electrophysiology. Hypoglycemia events that occur spontaneously or due to excess insulin administration threaten the lives of DM patients – with the increased risk of sudden death. However, the molecular underpinnings of hypoglycemia-aggravated DCM remain to be elucidated. Methods and Results: Here we used the established streptozotocin-induced type 1 diabetic cardiomyopathy (T1 DCM) murine model to investigate how hypoglycemia aggravates DCM progression. We showed that chronic hyper- or hypoglycemic challenges dampened cardiac diastolic function in vivo as well as myocardial contractility and calcium handling in isolated cardiomyocytes. Similar contractile defects were recapitulated using neonatal mouse ventricular myocytes (NMVMs) under glucose fluctuation challenges. Using immunoprecipitation mass spectrometry, we identified and validated that hypoglycemia challenge activates the MEK/ERK and PI3K/Akt pathways which results in Cx43 phosphorylation by Src protein in cardiomyocytes. Cx43 dissociation and accumulation at mitochondrial inner membrane was confirmed both in human and murine cardiomyocytes. To determine causality, we overexpressed a mitochondrial targeting Cx43 (mtCx43) using AAV2. At normal blood glucose levels, mtCx43 overexpression recapitulated cardiomyocytes contractile deficiencies, cardiac diastolic dysfunction as well as aberrant electrophysiology both in vitro as well as in vivo. Conclusions: Hypoglycemia challenges results in the accumulation of mtCx43 through the MEK/ERK/Src and PI3K/Akt/Src pathways. We provide evidence that Cx43 mislocalization is present in diabetes mellitus patient hearts, STZ-induced DCM murine model, and glucose fluctuation challenged NMVMs. Mechanistically, we demonstrated that mtCx43 is responsible for inducing aberrant contraction and disrupts electrophysiology in cardiomyocytes and our results support targeting of mtCx43 in treating DCM. Translational perspective: Severe hypoglycemia drives cardiac dysfunction and aggressive ventricular arrhythmias in patients with DCM that leads to sudden cardiac death. Here we demonstrate that Cx43 mislocalization to mitochondria occurs upon hypoglycemic challenge and mtCx43 accumulation is responsible for cardiac diastolic dysfunction, cardiomyocyte contractile dysfunction, and aberrant electrophysiology in vivo. Our findings give support for therapeutic targeting of MEK/ERK/Src and PI3K/Akt/Src pathways to prevent mtCx43-driven DCM.

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