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  1. Article ; Online: High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction

    Gurinder Bir Singh / Yang Zhang / Krishna M. Boini / Saisudha Koka

    International Journal of Molecular Sciences, Vol 20, Iss 14, p

    2019  Volume 3570

    Abstract: The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs’ progression are still unclear. In this ... ...

    Abstract The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs’ progression are still unclear. In this regard, high-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to disrupt cell−cell junctions, resulting in vascular endothelial hyper permeability leading to endothelial dysfunction. The present study tested whether TMAO associated endothelial dysfunction results via HMGB1 activation. Biochemical and RT-PCR analysis showed that TMAO increased the HMGB1 expression in a dose-dependent manner in endothelial cells. However, prior treatment with glycyrrhizin, an HMGB1 binder, abolished the TMAO-induced HMGB1 production in endothelial cells. Furthermore, Western blot and immunofluorescent analysis showed significant decrease in the expression of cell−cell junction proteins ZO-2, Occludin, and VE-cadherin in TMAO treated endothelial cells compared with control cells. However, prior treatment with glycyrrhizin attenuated the TMAO-induced cell−cell junction proteins’ disruption. TMAO increased toll-like receptor 4 (TLR4) expression in endothelial cells. Inhibition of TLR4 expression by TLR4 siRNA protected the endothelial cells from TMAO associated tight junction protein disruption via HMGB1. In conclusion, our results demonstrate that HMGB1 is one of the important mediators of TMAO-induced endothelial dysfunction.
    Keywords HMGB1 ; TMAO ; tight junction ; ZO2 ; glycyrrhizin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Simvastatin improves lysosome function via enhancing lysosome biogenesis in endothelial cells

    Youzhi Zhang / Yun-Ting Wang / Saisudha Koka / Yang Zhang / Tahir Hussain / Xiang Li

    Frontiers in Bioscience-Landmark, Vol 25, Iss 2, Pp 283-

    2020  Volume 298

    Abstract: Nlrp3 inflammasomes were shown to play a critical role in triggering obesity-associated early onsets of cardiovascular complications such as endothelial barrier dysfunction with endothelial hyperpermeability. Statins prevent endothelial dysfunction and ... ...

    Abstract Nlrp3 inflammasomes were shown to play a critical role in triggering obesity-associated early onsets of cardiovascular complications such as endothelial barrier dysfunction with endothelial hyperpermeability. Statins prevent endothelial dysfunction and decrease cardiovascular risk in patients with obesity and diabetes. However, it remains unclear whether statin treatment for obesity-induced endothelial barrier dysfunction is in part due to the blockade of Nlrp3 inflammasome signaling axis. The results showed that simvastatin, a clinically and widely used statin, prevented free fatty acid-induced endothelial hyperpermeability and disruption of ZO-1 and VE-cadherin junctions in mouse microvascular endothelial cells (MVECs). This protective effect of simvastatin was largely due to improved lysosome function that attenuated lysosome injury-mediated Nlrp3 inflammasome activation and subsequent release of high mobility group box protein-1 (HMGB1). Mechanistically, simvastatin induces autophagy that promotes removal of damaged lysosomes and also promotes lysosome regeneration that preserves lysosome function. Collectively, simvastatin treatment improves lysosome function via enhancing lysosome biogenesis and its autophagic turnover, which may be an important mechanism to suppress Nlrp3 inflammasome activation and prevents endothelial hyperpermeability in obesity.
    Keywords : free fatty acid ; inflammasome ; statin ; lysosome ; autophagy ; endothelial hyperpermeability ; Biochemistry ; QD415-436 ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher IMR Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Attenuation of Doxorubicin-induced Cardiotoxicity by Tadalafil

    Saisudha Koka / Rakesh C Kukreja

    Molecular and Cellular Pharmacology, Vol 2, Iss 5, Pp 173-

    A Long Acting Phosphodiesterase-5 Inhibitor

    2010  Volume 178

    Abstract: Doxorubicin (DOX) is a broad spectrum antineoplastic drug widely used in the treatment of several hematogenous and solid human malignancies. Despite its excellent clinical efficacy as a chemotherapeutic agent, its therapeutic usage has been restricted ... ...

    Abstract Doxorubicin (DOX) is a broad spectrum antineoplastic drug widely used in the treatment of several hematogenous and solid human malignancies. Despite its excellent clinical efficacy as a chemotherapeutic agent, its therapeutic usage has been restricted due to its cardiotoxicity. Phosphodiesterase-5 (PDE-5) inhibitors or erectile dysfunction drugs including sildenafil, have been shown to have powerful cardioprotective effect against injuries under a variety of experimental situations including ischemia/reperfusion injury, myocardial infarction and DOX-induced cardiomyopathy. We studied the effect of – tadalafil, a long acting PDE-5 inhibitor in preventing damage in the heart with DOX treatment. Our results showed that tadalafil improved left ventricular function and survival by attenuating DOX-induced apoptosis and cardiac oxidative stress without interfering with the anti-tumor efficacy of DOX in both in vitro and in vivo tumor models. Herein, we present an overview of our study, and consider the potential mechanisms by which tadalafil, at therapeutically relevant concentrations mediate beneficial cardioprotective effects in DOX cardiotoxicity. Based on our current and previously published studies, we propose that the class of PDE-5 inhibitors can represent a novel approach which can be exploited for achieving therapeutic benefit in the treatment of DOX-induced cardiotoxicity in patients.
    Keywords Doxorubicin ; Cardiomyopathy ; Phosphodiesterase inhibitors ; PKG ; cGMP ; ROS ; Therapeutics. Pharmacology ; RM1-950 ; Medicine ; R ; DOAJ:Therapeutics ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Subject code 610
    Language English
    Publishing date 2010-01-01T00:00:00Z
    Publisher LumiText Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Endothelial NLRP3 inflammasome activation and arterial neointima formation associated with acid sphingomyelinase during hypercholesterolemia

    Saisudha Koka / Min Xia / Yang Chen / Owais M. Bhat / Xinxu Yuan / Krishna M. Boini / Pin-Lan Li

    Redox Biology, Vol 13, Iss C, Pp 336-

    2017  Volume 344

    Abstract: The NLRP3 inflammasome has been reported to be activated by atherogenic factors, whereby endothelial injury and consequent atherosclerotic lesions are triggered in the arterial wall. However, the mechanisms activating and regulating NLRP3 inflammasomes ... ...

    Abstract The NLRP3 inflammasome has been reported to be activated by atherogenic factors, whereby endothelial injury and consequent atherosclerotic lesions are triggered in the arterial wall. However, the mechanisms activating and regulating NLRP3 inflammasomes remain poorly understood. The present study tested whether acid sphingomyelinase (ASM) and ceramide associated membrane raft (MR) signaling platforms contribute to the activation of NLRP3 inflammasomes and atherosclerotic lesions during hypercholesterolemia. We found that 7-ketocholesterol (7-Keto) or cholesterol crystal (ChC) markedly increased the formation and activation of NLRP3 inflammasomes in mouse carotid arterial endothelial cells (CAECs), as shown by increased colocalization of NLRP3 with ASC or caspase-1, enhanced caspase-1 activity and elevated IL-1β levels, which were markedly attenuated by mouse Asm siRNA, ASM inhibitor- amitriptyline, and deletion of mouse Asm gene. In CAECs with NLRP3 inflammasome formation, membrane raft (MR) clustering with NADPH oxidase subunits was found remarkably increased as shown by CTXB (MR marker) and gp91phox aggregation indicating the formation of MR redox signaling platforms. This MR clustering was blocked by MR disruptor (MCD), ROS scavenger (Tempol) and TXNIP inhibitor (verapamil), accompanied by attenuation of 7-Keto or ChC-induced increase in caspase-1 activity. In animal experiments, Western diet fed mice with partially ligated left carotid artery (PLCA) were found to have significantly increased neointimal formation, which was associated with increased NLRP3 inflammasome formation and IL-1β production in the intima of Asm+/+ mice but not in Asm-/- mice. These results suggest that Asm gene and ceramide associated MR clustering are essential to endothelial inflammasome activation and dysfunction in the carotid arteries, ultimately determining the extent of atherosclerotic lesions.
    Keywords Inflammasome ; Ceramide ; Acid sphingomyelinase ; Atherosclerosis ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2017-10-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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