Dapagliflozin and Ticagrelor Have Additive Effects on the Attenuation of the Activation of the NLRP3 Inflammasome and the Progression of Diabetic Cardiomyopathy: an AMPK–mTOR Interplay

Chen, Huan; Tran, Da T.; Yang, Hsiu Chiung; Nylander, Sven; Birnbaum, Yochai; Ye, Yumei

doi:10.1007/s10557-020-06978-y

Cited by 63 publications

(43 citation statements)

References 46 publications

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“…In spite of initially considered to be a hypoglycemic agent, the effects of Dap have extended far beyond that which is now being considered for improving chronic kidney disease and heart failure, even in people without DM. Similarly with the results acquired from the high fat diet and low dose STZ-induced diabetic rats, ob/ob mice, and db/db mice ( Ye et al, 2017 ; Giuliani, 2019 ; Arow et al, 2020 ; Chen et al, 2020 ), the present study demonstrated that treatment with Dap for 8 weeks successfully improved cardiac dysfunction and reduced myocardial fibrosis and apoptosis in STZ-induced diabetic mice. Recent studies show that SGLT2 inhibitors increase the excretions of urinary glucose and urinary sodium in type 2 diabetic GK and OLETF rats ( Chung et al, 2019 ; Masuda et al, 2020 ).…”

Section: Discussionsupporting

confidence: 86%

“…Rising evidences have proved that Dap declines the rate of both cardiovascular death and heart failure hospitalization ( McMurray et al, 2019 ; Wiviott et al, 2019 ). Recently, Dap has been proved to reduce myocardial NLRP3 inflammasome activation, and to improve the aggravation of left ventricular ejection fraction in ob/ob type 2 DM mice ( Ye et al, 2017 ; Chen et al, 2020 ). Arow et al (2020) reported that Dap decreases myocardial inflammation and reactive oxygen species (ROS) production in db/db type 2 DM mice and isolated cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

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A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

et al. 2021

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Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). One of the hallmarks of the DCM is enhanced oxidative stress in myocardium. The aim of this study was to research the underlying mechanisms involved in the effects of dapagliflozin (Dap) on myocardial oxidative stress both in streptozotocin-induced DCM rats and rat embryonic cardiac myoblasts H9C2 cells exposed to high glucose (33.0 mM). In in vivo studies, diabetic rats were given Dap (1 mg/ kg/ day) by gavage for eight weeks. Dap treatment obviously ameliorated cardiac dysfunction, and improved myocardial fibrosis, apoptosis and oxidase stress. In in vitro studies, Dap also attenuated the enhanced levels of reactive oxygen species and cell death in H9C2 cells incubated with high glucose. Mechanically, Dap administration remarkably reduced the expression of membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits gp91phox and p22phox, suppressed the p67phox subunit translocation to membrane, and decreased the compensatory elevated copper, zinc superoxide dismutase (Cu/Zn-SOD) protein expression and total SOD activity both in vivo and in vitro. Collectively, our results indicated that Dap protects cardiac myocytes from damage caused by hyperglycemia through suppressing NADPH oxidase-mediated oxidative stress.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

et al. 2021

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“…The results showed that both dapagliflozin and ticagrelor attenuated the progression of diabetic cardiomyopathy, NLRP3 inflammasome activation and fibrosis in BTBR mice, and that the combination had an additive effect. 94 …”

Section: Role Of Pyroptosis In Cardiovascular Diseasementioning

confidence: 99%

Pyroptosis: A New Regulating Mechanism in Cardiovascular Disease

Ji¹,

Qi²,

Wang³

et al. 2021

JIR

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Pyroptosis is a kind of pro-inflammatory cell death. Compared with autophagy and apoptosis, pyroptosis has unique characteristics in morphology and mechanism. Specifically, pyroptosis is a kind of cell lysis mediated by the Gasdermin family, releases inflammatory cytokines IL-1β and IL-18. There are three different forms of mechanism, which are caspase-1-mediated, caspase-4/5/11-mediated and caspase-3-mediated. A large number of studies have proved that pyroptosis is closely related to cardiovascular disease. This paper reviewed the recent progress in the related research on pyroptosis and myocardial infarction, ischemia-reperfusion, atherosclerosis, diabetic cardiomyopathy, arrhythmia, heart failure hypertension and Kawasaki disease. Therefore, we believe that pyroptosis may be a new therapeutic target in the cardiovascular field.

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“…Saxagliptin has been found also to attenuate myocardial I/R injury in db/db mice (a genetic model of diabetes), via inhibition of ERK/TLR4/NLRP3 and p38/miR‐146b/TLR4/NLRP3 pathways, suggesting that DPP‐4 inhibition blocks the first step underlying inflammasome activation 142,143 . Two recent papers by Yang et al 144 and Chen et al 145 showed that dapagliflozin and metformin attenuated the progression of diabetic CM through the inhibition of NLRP3 signaling via activation of the AMPK system and consequent inhibition of mTOR (mechanistic target of rapamycin). In addition, cotreatment with ticagrelor, a P2Y12 receptor antagonist employed for the prevention of atherothrombotic events in patients with acute coronary syndromes, attenuated further diabetic CM in mice by improving left ventricular end‐systolic and end‐diastolic volumes, left ventricular ejection fraction, cardiac inflammation, and remodelling 145 …”

Section: Effects Of the Pharmacological Modulation Of Nlrp3 Inflammasome In Cardiovascular Diseasesmentioning

confidence: 99%

NLRP3 inflammasome in cardiovascular diseases: Pathophysiological and pharmacological implications

Pellegrini

Martelli

Antonioli

et al. 2021

Medicinal Research Reviews

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Growing evidence points out the importance of nucleotide‐binding oligomerization domain leucine‐rich repeat and pyrin domain‐containing protein 3 (NLRP3) inflammasome in the pathogenesis of cardiovascular diseases (CVDs), including hypertension, myocardial infarct (MI), ischemia, cardiomyopathies (CMs), heart failure (HF), and atherosclerosis. In this regard, intensive research efforts both in humans and in animal models of CVDs are being focused on the characterization of the pathophysiological role of NLRP3 inflammasome signaling in CVDs. In addition, clinical and preclinical evidence is coming to light that the pharmacological blockade of NLRP3 pathways with drugs, including novel chemical entities as well as drugs currently employed in the clinical practice, biologics and phytochemicals, could represent a suitable therapeutic approach for prevention and management of CVDs. On these bases, the present review article provides a comprehensive overview of clinical and preclinical studies about the role of NLRP3 inflammasome in the pathophysiology of CVDs, including hypertension, MI, ischemic injury, CMs, HF and atherosclerosis. In addition, particular attention has been focused on current evidence on the effects of drugs, biologics, and phytochemicals, targeting different steps of inflammasome signaling, in CVDs.

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Dapagliflozin and Ticagrelor Have Additive Effects on the Attenuation of the Activation of the NLRP3 Inflammasome and the Progression of Diabetic Cardiomyopathy: an AMPK–mTOR Interplay

Cited by 63 publications

References 46 publications

A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

Pyroptosis: A New Regulating Mechanism in Cardiovascular Disease

NLRP3 inflammasome in cardiovascular diseases: Pathophysiological and pharmacological implications

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