Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

Wang, Yabin; Ma, Sai; Wang, Qiang; Hu, Wenzhi; Wang, Dongjuan; Li, Xiujuan; Su, Tao; Qin, Xing; Zhang, Xiaotian; Ma, Ke; Chen, JiangWei; Xiong, Lize; Cao, Feng

doi:10.1007/s11427-013-4604-z

Cited by 47 publications

(37 citation statements)

References 19 publications

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“…In response to chronic pressure the -actinin-binding muscle LIM protein (MLP) translocates from the cytoplasm to the nucleus. MLP in the nucleus stimulates myogenic differentiation through binding to the muscle-specific transcription factor MyoD, which enhances transcriptional activity of the downstream targets (Wang et al, 2014;. In our previous study, Kindlin-2 translocates into nucleus to form a tripartite complex with active -catenin and TCF4 and regulates myogenic regulatory factor myogenin via a canonical Wnt/-catenin signaling (Wu et al, 2015;Yu et al, 2013).…”

Section: Discussionmentioning

confidence: 95%

Depletion of Kindlin-2 induces cardiac dysfunction in mice

Liu

Chi

et al. 2016

Sci. China Life Sci.

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Kindlin-2, a member of the Kindlin family focal adhesion proteins, plays an important role in cardiac development. It is known that defects in the Z-disc proteins lead to hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Our previous investigation showed that Kindlin-2 is mainly localized at the Z-disc and depletion of Kindlin-2 disrupts the structure of the Z-Disc. Here, we reported that depletion of Kindlin-2 leads to the disordered myocardial fibers, fractured and vacuolar degeneration in myocardial fibers. Interestingly, depletion of Kindlin-2 in mice induced cardiac myocyte hypertrophy and increased the heart weight. Furthermore, decreased expression of Kindlin-2 led to cardiac dysfunction and also markedly impairs systolic function. Our data indicated that Kindlin-2 not only maintains the cardiac structure but also is required for cardiac function.

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Section: Discussionmentioning

confidence: 95%

Depletion of Kindlin-2 induces cardiac dysfunction in mice

Liu

Chi

et al. 2016

Sci. China Life Sci.

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“…We tested the lower dose of 4 mg·kg −1 and found this lower dose caused no significant weight change but tended to improve mice survival (Figure S1a). For AM1241, a previous study used the dose of 20 mg·kg −1 in an infarcted mouse model (Wang et al, ). We initially tested this dose and found that the beneficial effects of AM1241 at this dose were not significant.…”

Section: Methodsmentioning

confidence: 99%

Opposite effects of cannabinoid CB₁ and CB₂ receptors on antipsychotic clozapine‐induced cardiotoxicity

Dong

et al. 2019

British J Pharmacology

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Background and Purpose: Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis, but the risk of severe cardiotoxicity limits its clinical use. The present study investigated the harmful effects of clozapine on myocardium and assessed the involvement of cannabinoid receptors in its cardiotoxicity.Experimental Approach: Clozapine alone or in combination with selective cannabinoid receptor antagonists or agonists were used to treat mice and cardiomyocytes.Key Results: Clozapine induced myocardial inflammation and infiltration 7 days after i.p. injection. Mice survival rate and myocardial infiltration, and fibrotic lesions were dose-dependently worsened by clozapine. Clozapine decreased major endocannabinoid levels in sera and cultured cardiomyocytes. Cannabinoid CB 1 receptors decreased in clozapine-treated hearts and were translocated from cytomembranes to cytoplasm and nuclei, whereas CB 2 receptors increased in clozapinetreated hearts and inversely translocated from nuclei to the cytomembrane. Selective antagonists of CB 1 receptors, rimonabant and AM281, but not its selective agonist arachidonyl-2′-chloroethylamide, ameliorated clozapine-induced myocardial inflammatory infiltration and fibrotic lesions. In contrast, selective agonists of CB 2 receptors, AM1241 and JWH-133, but not its selective antagonist AM630, blunted clozapine-mediated cardiotoxicity in mice. In cultured cardiomyocytes, clozapine increased the pro-inflammatory factor IL-1β and the concentrations of myocardial injury markers (LDH and aspartate aminotransferase); these effects were reversed by either a CB 1 antagonist or CB 2 agonist and further prevented by combined pretreatments.Conclusions and Implications: Our data provide evidence that cannabinoid CB 1 and CB 2 receptors have opposite effects and selective antagonists of CB 1 or agonists of CB 2 receptors might confer protective effects against clozapine in myocardium.

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“…The study of Zhi et al describes that wortmannin significantly decreases the expression of collagen type I in adult rat cardiac fibroblasts (Zhi, et al, 2013). On the other hand, Wang et al show that wortmannin cancels the effects of cannabinoid receptor type 2 agonist including improving cardiac function, decreasing fibrosis and reducing inflammatory cytokine secretion and oxidative stress in a mouse model with infarcted heart (Wang, et al, 2014). Lastly, Zhang and others also identify that wortmannin abolishes zinc's anti-fibrotic capacity in a rat kidney tubular epithelial cell line .…”

Section: Highlighting Anti-fibrotic Drug Candidatesmentioning

confidence: 99%

Drug Repurposing Through a Bioinformatics Pipeline Applied on Fibrotic Diseases

Karatzas¹,

Kakouri

Kolios

et al. 2020

Preprint

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AbstractSubjectFibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues. Idiopathic Pulmonary Fibrosis (IPF), an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target.ObjectiveWe highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among nine fibrotic diseases. We bibliographically explore the resulting candidate substances for potential anti-fibrotic mode of action and focus on diseases that appear to be more similar to IPF so as to jointly examine potential treatments.MethodologyWe identify key genes for the 9 fibrotic diseases by analyzing transcriptomics datasets. We construct gene-to-gene networks for each disease and examine these networks to explore functional communities of biological pathways. We also use the most significant genes as input in Drug Repurposing (DR) tools and re-rank the resulting candidates according to their structural properties and functional relationship to each investigated disease.ResultsWe identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our DR results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven’t been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted for Oral Submucous Fibrosis (OSF). We suggest digoxin to be tested against OSF, since we observe cardiomyopathy-related pathways implicated in OSF and there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish that IPF shares several involved genes, biological pathways and candidate inhibiting-drugs with Dupuytren’s Disease, IgG4-related Disease, SSc and Cystic Fibrosis. We propose that treatments for these fibrotic diseases should be jointly pursued.

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Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

Cited by 47 publications

References 19 publications

Depletion of Kindlin-2 induces cardiac dysfunction in mice

Depletion of Kindlin-2 induces cardiac dysfunction in mice

Opposite effects of cannabinoid CB₁ and CB₂ receptors on antipsychotic clozapine‐induced cardiotoxicity

Drug Repurposing Through a Bioinformatics Pipeline Applied on Fibrotic Diseases

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Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

Cited by 47 publications

References 19 publications

Depletion of Kindlin-2 induces cardiac dysfunction in mice

Depletion of Kindlin-2 induces cardiac dysfunction in mice

Opposite effects of cannabinoid CB1 and CB2 receptors on antipsychotic clozapine‐induced cardiotoxicity

Drug Repurposing Through a Bioinformatics Pipeline Applied on Fibrotic Diseases

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Opposite effects of cannabinoid CB₁ and CB₂ receptors on antipsychotic clozapine‐induced cardiotoxicity