Targeting Aldh2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility

Li, Chen; Yang, Zuozhang; Yu, Lu; Ma, Heng

doi:10.1016/j.pathophys.2018.07.029

Cited by 8 publications

(12 citation statements)

References 23 publications

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“…Besides, ALDH2 has been demonstrated in another research to mediate the protection of chronic ethanol against endothelial senescence through the SIRT1 pathway in vitro [50]. In the model of myocardial ischaemia/reperfusion (MI/R) injury, cardiacspecific ALDH2 upregulation by viral gene delivery significantly ameliorated chronic-pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury [51]. These findings together indicate that SIRT1 might be a downstream regulator of ALDH2-induced effects.…”

Section: Discussionmentioning

confidence: 82%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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Background: Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats. Methods: Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted. Results: Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein.Conclusions: Together, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.

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Section: Discussionmentioning

confidence: 82%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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“…After recombination, minicircle quality was confirmed by gel blotting and sequencing. Twenty five micro gram of shRNA targeting MT1 or MT2 or sh‐Control minicircle vector was transferred via aortic cross‐clamping as formerly described . After dissection of the aorta and pulmonary artery, minicircle vectors were injected into the left ventricular cavity by a 31‐G catheter while the aorta and pulmonary artery were temporarily cross‐clamped for 30 seconds.…”

Section: Methodsmentioning

confidence: 99%

“…Five weeks after AAV9 delivery, MT1 and MT2 overexpression was verified by immunohistochemistry and Western blot. The remaining mice were subjected to MI/R We chose five weeks after AAV9 injection as the optimal timing since previous studies reported 4‐6 weeks as the time needed for AAV9 to achieve optimal transfection effect in the myocardium …”

Section: Methodsmentioning

confidence: 99%

“…Twenty five micro gram of shRNA targeting MT1 or MT2 or sh-Control minicircle vector was transferred via aortic cross-clamping as formerly described. 28,29 After dissection of the aorta and pulmonary artery, minicircle vectors were injected into the left ventricular cavity by a 31-G catheter while the aorta and pulmonary artery were temporarily cross-clamped for 30 seconds. This operation allows minicircle vector solution to circulate down the coronary arteries and perfuse the heart thoroughly.…”

Section: Minicircle-mediated Cardiac-specific Gene Silencingmentioning

confidence: 99%

“…The remaining mice were subjected to MI/R We chose five weeks after AAV9 injection as the optimal timing since previous studies reported 4-6 weeks as the time needed for AAV9 to achieve optimal transfection effect in the myocardium. 29,30 2.6 | Echocardiography and hemodynamic assessment for evaluation of cardiac function M-mode echocardiography was accomplished with an echocardiography system with a 15-MHz linear transducer (Vevo 2100; VisualSonics, Canada) as we previously described. 31 Left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and the maximal rates of increase and decrease in LV pressure (+dP/dtmax and -dP/ dtmax) during the cardiac cycle were measured using a Millar pressure catheter as we previously described.…”

Section: In Vivo Aav9-mediated Cardiomyocytespecific Gene Overexprementioning

confidence: 99%

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Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Han

Wang

Chen

et al. 2019

Journal of Pineal Research

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Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin‐conferred cardioprotection remains unclear. In this study, we employed both loss‐of‐function and gain‐of‐function approaches to reveal the answer. Mice (wild‐type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild‐type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R‐initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2‐silenced heart, but not the MT1 subtype. Furthermore, AAV9‐mediated cardiomyocyte‐specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.

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Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

Tian¹,

Ma²,

Yin³

et al. 2020

Aging and disease

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Aging is a pivotal risk factor for developing cardiovascular diseases (CVD) due to the lifelong exposure to various risk factors that may affect the heart and vasculature during aging. AMP-activated protein kinase (AMPK), a serine/threonine protein kinase, is a pivotal endogenous energy regulator that protects against various pathological alterations. In this report, we first introduced the protective mechanisms of AMPK signaling in myocardium, such as oxidative stress, apoptosis, inflammation, autophagy and inflammatory response. Next, we introduced the potential correlation between AMPK and cardiac aging. Then, we highlighted the roles of AMPK signaling in cardiovascular diseases, including myocardial ischemia, cardiomyopathy, and heart failure. Lastly, some potential directions and further perspectives were expanded. The information extends our understanding on the protective roles of AMPK in myocardial aging, which may contribute to the design of drug targets and sheds light on potential treatments of AMPK for aging-related CVD.

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Targeting Aldh2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility

Cited by 8 publications

References 23 publications

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

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