Melatonin attenuates chronic pain related myocardial ischemic susceptibility through inhibiting RIP3-MLKL/CaMKII dependent necroptosis

Yang, Zuozhang; Li, Chen; Wang, Yishi; Yang, Jingrun; Yin, Yulong; Liu, Manling; Shi, Zhaoling; Ma, Nan; Yu, Lu; Ma, Heng

doi:10.1016/j.yjmcc.2018.10.018

Cited by 53 publications

(48 citation statements)

References 56 publications

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“…Recently it has been described that necroptosis can proceed in a RIP 1 independent pathway, activating Ca 2+ -CamKII to regulate mitochondrial permeability transition pore (mPTP) opening 54,55 . The opening of the mPTP in response to ischemia-reperfusion injury has been linked to cell death in the heart and other organs 56,57 .…”

Section: Bpa Induced Vascular Injury Is Mediated By Rip3/camkii Depenmentioning

confidence: 99%

Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway

Reventún¹,

Sánchez-Esteban²,

Cook³

et al. 2020

Sci Rep

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Epidemiological studies link long term exposure to xenoestrogen Bisphenol-A to adverse cardiovascular effects. Our previous results show that BPA induces hypertension by a mechanism involving CamKII activation and increased redox stress caused by eNOS uncoupling. Recently, CamKII sustained activation has been recognized as a central mediator of programmed cell death in cardiovascular diseases, including necroptosis. However, the role of necroptosis in cardiac response to BPA had not yet been explored. Mice exposed to BPA for 16 weeks showed altered heart function, electrical conduction, and increased blood pressure. Besides, a stress test showed ST-segment depression, indicative of cardiac ischemia. The hearts exhibited cardiac hypertrophy and reduced vascularization, interstitial edema, and large hemorrhagic foci accompanied by fibrinogen deposits. BPA initiated a cardiac inflammatory response, up-regulation of M1 macrophage polarization, and increased oxidative stress, coinciding with the increased expression of CamKII and the necroptotic effector RIP3. In addition, cell death was especially evident in coronary endothelial cells within hemorrhagic areas, and Evans blue extravasation indicated a vascular leak in response to Bisphenol-A. Consistent with the in vivo findings, BPA increased the necroptosis/apoptosis ratio, the expression of RIP3, and CamKII activation in endothelial cells. Necrostatin-1, an inhibitor of necroptosis, alleviated BPA induced cardiac dysfunction and prevented the inflammatory and hemorrhagic response in mice. Mechanistically, silencing of RIP3 reversed BPA-induced necroptosis and CamKII activation in endothelial cells, while inhibition of CamKII activation by KN-93 had no effect on RIP3 expression but decreased necroptotic cell death suggesting that BPA induced necroptosis is mediated by a RIP 3/CamKII dependent pathway. Our results reveal a novel pathogenic role of BPA on the coronary circulation. BPA induces endothelial cell necroptosis, promotes the weakening of coronary vascular wall, which caused internal ventricular hemorrhages, delaying the reparative process and ultimately leading to cardiac dysfunction.

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Section: Bpa Induced Vascular Injury Is Mediated By Rip3/camkii Depenmentioning

confidence: 99%

Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway

Reventún¹,

Sánchez-Esteban²,

Cook³

et al. 2020

Sci Rep

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“…In a murine chronic pain induced by spared nerve injury model followed by myocardial ischemia-reperfusion, melatonin attenuated chronic pain related myocardial ischemic susceptibility through inhibiting RIP3-MLKL/CaMKII dependent necroptosis 20 mg/kg i.p. mg (113) In a rat model of cardiac ischemia/reperfusion after ligation of descending coronary artery melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on mitochondrial fusion/mitophagy 20 mg/kg i.p. 120 mg (114) As in the case of Table 1, the HED of melatonin for a 75 kg adult calculated by normalization of body surface area (43) yielded values greater than 60 mg/day (Table 2).…”

Section: Mg (79)mentioning

confidence: 99%

Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

Cardinali

2019

Melatonin Res.

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This review article discusses the special role that melatonin, a molecule with chronobiotic/cytoprotective properties, may have in prevention and treatment of the metabolic syndrome (MS), ischemic and non-ischemic cardiovascular diseases and Alzheimer´s disease (AD). Prevention of these diseases is a major goal for governmental and non-governmental organizations, and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. In humans, circulating melatonin levels are consistently reduced in MS, ischemic and non-ischemic cardiovascular diseases and AD, the potential therapeutic value of melatonin being suggested by a limited number of clinical trials generally employing melatonin in the 2-5 mg/day range. In animal model studies of MS, ischemic and non-ischemic cardiovascular diseases and AD melatonin was very effective to curtail symptomatology. However, calculations derived from animal studies indicate projected cytoprotective melatonin doses for humans in the 40-100 mg/day range, doses that are rarely employed clinically. Hence, controlled studies employing melatonin doses in this range are urgently needed. Since the pharmaceutical industry is refractive to support them because of the lack of protective patents for a natural compound, only the involvement of governmental and non-profit organizations can achieve that goal. Within this prospect, the off-label use of melatonin is discussed.

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“…17,99,100 Growing evidence suggests that melatonin administration may reverse the nociceptive threshold in spinal nerve ligation (SNL) rodents. 101,102 Meanwhile, MT2 receptor-selective antagonist treatment reverses the effect caused by melatonin, suggesting that MT2 receptors may be a novel target in treating neuropathic pain. 15,103,104…”

Section: Neuropathic Painmentioning

confidence: 99%

<p>Role of Melatonin in the Regulation of Pain</p>

Xie

Fan

et al. 2020

JPR

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Melatonin is a pleiotropic hormone synthesized and secreted mainly by the pineal gland in vertebrates. Melatonin is an endogenous regulator of circadian and seasonal rhythms. Melatonin is involved in many physiological and pathophysiological processes demonstrating antioxidant, antineoplastic, anti-inflammatory, and immunomodulatory properties. Accumulating evidence has revealed that melatonin plays an important role in pain modulation through multiple mechanisms. In this review, we examine recent evidence for melatonin on pain regulation in various animal models and patients with pain syndromes, and the potential cellular mechanisms.

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Melatonin attenuates chronic pain related myocardial ischemic susceptibility through inhibiting RIP3-MLKL/CaMKII dependent necroptosis

Cited by 53 publications

References 56 publications

Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway

Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway

Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

<p>Role of Melatonin in the Regulation of Pain</p>

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