Inhibition of Pyk2 and Src activity improves Cx43 gap junction intercellular communication

Li, Zheng; Trease, Andrew J.; Katsurada, Kenichi; Spagnol, Gaëlle; Li, Hanjun; Shi, Wen; Duan, Bin; Patel, Kaushik P.; Sorgen, Paul L.

doi:10.1016/j.yjmcc.2020.09.004

Cited by 15 publications

(40 citation statements)

References 91 publications

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“…Indeed, the expression of PKCε was increased in hairless SHR M males and MAPK42/44 in SHR M females vs. sex-matched wild type SHR, while the expression of PKA was lower in hairless SHR M males vs. wild type SHR. These differences are challenging for further research, since the overexpression of protein kinases may increase Cx43 phosphorylation and vice versa, thereby impacting the channel function [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Cardiac Cx43 Signaling Is Enhanced and TGF-β1/SMAD2/3 Suppressed in Response to Cold Acclimation and Modulated by Thyroid Status in Hairless SHRM

et al. 2022

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The hearts of spontaneously hypertensive rats (SHR) are prone to malignant arrhythmias, mainly due to disorders of electrical coupling protein Cx43 and the extracellular matrix. Cold acclimation may induce cardio-protection, but the underlying mechanisms remain to be elucidated. We aimed to explore whether the adaptation of 9-month-old hairless SHRM to cold impacts the fundamental cardiac pro-arrhythmia factors, as well as the response to the thyroid status. There were no significant differences in the registered biometric, redox and blood lipids parameters between hairless (SHRM) and wild type SHR. Prominent findings revealed that myocardial Cx43 and its variant phosphorylated at serine 368 were increased, while an abnormal cardiomyocyte Cx43 distribution was attenuated in hairless SHRM vs. wild type SHR males and females. Moreover, the level of β-catenin, ensuring mechanoelectrical coupling, was increased as well, while extracellular matrix collagen-1 and hydroxyproline were lower and the TGF-β1 and SMAD2/3 pathway was suppressed in hairless SHRM males compared to the wild type strain. Of interest, the extracellular matrix remodeling was less pronounced in females of both hypertensive strains. There were no apparent differences in response to the hypothyroid or hyperthyroid status between SHR strains concerning the examined markers. Our findings imply that hairless SHRM benefit from cold acclimation due to the attenuation of the hypertension-induced adverse downregulation of Cx43 and upregulation of extracellular matrix proteins.

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Section: Discussionmentioning

confidence: 99%

Cardiac Cx43 Signaling Is Enhanced and TGF-β1/SMAD2/3 Suppressed in Response to Cold Acclimation and Modulated by Thyroid Status in Hairless SHRM

et al. 2022

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“…In accordance to our previous observation (29), we find that hypoglycemia activates Src via MEK/ERK and PI3K/Akt pathways, which results in mtCx43 accumulation. Interestingly, Src has been implicated in Cx43 dysregulation in the heart (42)(43)(44)(45), but most studies attributed cardiac dysfunction to loss of cell-cell junction. Here, we demonstrate that in presence of intact cell-cell junctions and absence of hypoglycemia, overexpression of mtCx43 induced diastolic dysfunction and increase the risk of arrhythmia susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Hypoglycemia-Exacerbated Mitochondrial Connexin 43 Accumulation Aggravates Cardiac Dysfunction in Diabetic Cardiomyopathy

Wei

Chang

et al. 2022

Front. Cardiovasc. Med.

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BackgroundDiabetic cardiomyopathy (DCM) is a complex multifaceted disease responsible for elevated heart failure (HF) morbidity and mortality in patients with diabetes mellitus (DM). Patients with DCM exhibit subclinical diastolic dysfunction, progression toward systolic impairment, and abnormal electrophysiology. Hypoglycemia events that occur spontaneously or due to excess insulin administration threaten the lives of patients with DM—with the increased risk of sudden death. However, the molecular underpinnings of this fatal disease remain to be elucidated.Methods and ResultsHere, we used the established streptozotocin-induced DCM murine model to investigate how hypoglycemia aggravates DCM progression. We confirmed connexin 43 (Cx43) dissociation from cell–cell interaction and accumulation at mitochondrial inner membrane both in the cardiomyocytes of patients with DM and DCM murine. Here, we observed that cardiac diastolic function, induced by chronic hyperglycemia, was further aggravated upon hypoglycemia challenge. 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 mitogen-activated protein kinase kinase (MAPK kinase) (MEK)/extracellular regulated protein kinase (ERK) and inhibits phosphoinositide 3-kinase (PI3K)/Akt pathways, which results in Cx43 phosphorylation by Src protein and translocation to mitochondria in cardiomyocytes. To determine causality, we overexpressed a mitochondrial targeting Cx43 (mtCx43) using adeno-associated virus serotype 2 (AAV2)/9. At normal blood glucose levels, mtCx43 overexpression recapitulated cardiac diastolic dysfunction as well as 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.ConclusionDCM presents compensatory adaptation of mild mtCx43 accumulation, yet acute hypoglycemia challenges result in further accumulation of mtCx43 through the MEK/ERK/Src and PI3K/Akt/Src pathways. We provide evidence that Cx43 mislocalization is present in hearts of patients with DM 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.

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“…Blockage of SRC can stabilize Flk/cadherin complexing, reduce edema as well as tissue damage after myocardial infarction [ 29 ]. Additionally, SRC suppression reverses Cx43 remodeling and improves heart function following myocardial infarction [ 30 ]. CTNNB1 protein product β -catenin is a key integral part of the canonical Wnt/ β -catenin pathway.…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Analyses of the Pharmacological Targets and Therapeutic Mechanisms of Salvianolic Acid A in Myocardial Infarction

Huang

Zhang

Tang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. Salvianolic acid A, a natural polyphenolic ingredient extracted from traditional Chinese medicine, possesses an excellent pharmacological activity against cardiovascular diseases. Herein, therapeutic mechanisms of salvianolic acid A in myocardial infarction were explored through systematic and comprehensive network pharmacology analyses. Methods. The chemical structure of salvianolic acid A was retrieved from PubChem database. Targets of salvianolic acid A were estimated through SwissTargetPrediction, HERB, and TargetNet databases. Additionally, by GeneCards, OMIM, DisGeNET, and TTD online tools, myocardial infarction-relevant targets were predicted. Following intersection, therapeutic targets were determined. The interaction of their products was evaluated with STRING database, and hub therapeutic targets were selected. GO and KEGG enrichment analyses of therapeutic targets were then implemented. H9C2 cells were exposed to oxygen‐glucose deprivation/reoxygenation (OGD/R) to mimic myocardial infarction and administrated with salvianolic acid A. Cellular proliferation was assayed via CCK‐8 assay, and hub therapeutic targets were verified with RT-qPCR. Results. In total, 120 therapeutic targets of salvianolic acid A in myocardial infarction were identified. There were close interactions between their products. Ten hub therapeutic targets were determined, covering SRC, CTNNB1, PIK3CA, AKT1, RELA, EGFR, FYN, ITGB1, MAPK8, and NFKB1. Therapeutic targets were significantly correlated to myocardial infarction-relevant pathways, especially PI3K-Akt signaling pathway. Salvianolic acid A administration remarkably ameliorated the viability of OGD/R-induced H9C2 cells, and altered the expression of hub therapeutic targets. Conclusion. Our work uncovers therapeutic mechanisms of salvianolic acid A for the treatment of myocardial infarction, providing a new insight into further research on salvianolic acid A.

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Inhibition of Pyk2 and Src activity improves Cx43 gap junction intercellular communication

Cited by 15 publications

References 91 publications

Cardiac Cx43 Signaling Is Enhanced and TGF-β1/SMAD2/3 Suppressed in Response to Cold Acclimation and Modulated by Thyroid Status in Hairless SHRM

Cardiac Cx43 Signaling Is Enhanced and TGF-β1/SMAD2/3 Suppressed in Response to Cold Acclimation and Modulated by Thyroid Status in Hairless SHRM

Hypoglycemia-Exacerbated Mitochondrial Connexin 43 Accumulation Aggravates Cardiac Dysfunction in Diabetic Cardiomyopathy

Network Pharmacology Analyses of the Pharmacological Targets and Therapeutic Mechanisms of Salvianolic Acid A in Myocardial Infarction

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