Homocysteine ameliorates the endothelium-independent hypoxic vasoconstriction via the suppression of phosphatidylinositol 3-kinase/Akt pathway in porcine coronary arteries

An, Yuan-Ming; Feng, Han‐Zhong; Zhang, Xingzhong; Cong, Xin; Zhao, Qian; Wu, Li‐Ling; Dou, Dou

doi:10.1016/j.bbrc.2017.03.022

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…In addition, the PI3K-AKT-mTOR pathway was proven to be involved in the regulation of autophagy in NSCs 8 . The inhibitory role of Hcy in the PI3K-AKT signal pathway has been observed in vascular endothelial cells 36,37 . However, the regulation of Hcy on PI3K-AKT-mTOR was not reported in NSCs.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

et al. 2019

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The elevated level of the amino acid metabolite homocysteine (Hcy) is known as a risk factor for ischemic stroke. The molecular mechanisms responsible for neurotoxicity of Hcy remain largely unknown in ischemic brains. The previous studies have shown that Hcy decreases the proliferation and viability of neural stem cells (NSCs) in vivo and in vitro. Autophagy is required for the maintenance of NSCs homeostasis. In the current study, we hypothesized that the toxic effect of Hcy on NSCs may involve the changes in autophagy level following cerebral ischemia/reperfusion injury. The results showed that Hcy reduced cell viability, increased LDH release, and induced nonapoptotic cell death in primary NSCs exposed to oxygen–glucose deprivation)/reoxygenation (OGD/R). Treatment with autophagy inhibitor 3-methyladenine (3MA) partly reversed the decrease in the viability and prevented LDH release triggered by Hcy combined with OGD/R. Increased punctate LC3 dots co-localizing with Nestin-stained NSCs were also observed in the subventricular zone of Hcy-treated MCAO animals, which were partially blocked by 3MA. In vitro studies further revealed that Hcy induced the formation of autophagosomes, markedly increased the expression of the autophagic markers and decreased p-ERK, p-PI3K, p-AKT, and p-mTOR levels. In addition, MHY1485, an activator of mTOR, reduced Hcy-induced increase in LC3 and Beclin 1 protein levels, meanwhile ERK and PI3K activators (TPA, curcumin for ERK and IGF-1 for PI3K, respectively) enhanced Hcy-triggered mTOR inhibition in OGD/R NSCs. Our findings suggest that Hcy may cause excessive autophagy by downregulation of both PI3K-AKT- and ERK- dependent mTOR signaling, thereby facilitates the toxicity of Hcy on NSCs in ischemic brains.

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Section: Discussionmentioning

confidence: 99%

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

et al. 2019

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“…PI3K is involved in platelet activation signaling triggered by G-protein coupled receptors [ 28 ] and is required for platelet-induced aggregation induced by thrombin and thromboxane A2 (TxA2) [ 39 ]. PI3K/Akt signaling has been observed in regulation of vascular tone, or the degree of vasoconstriction experienced by a blood vessel, in both vascular endothelium and smooth muscle cells [ 40 ]. Exposure to homocysteine, a well-documented risk factor for atherosclerosis and stroke [ 41 , 42 ], in endothelial cells can form the intermediate S-nitroso-homocysteine, a vasodilator implicated in reducing vascular tone and altering arteriole calcium levels [ 40 ] Collectively, these associations have identified a novel association with ZDHHC6 and implicate PI3K/Akt signaling in time to stroke and/or vascular event following stroke [ 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…PI3K/Akt signaling has been observed in regulation of vascular tone, or the degree of vasoconstriction experienced by a blood vessel, in both vascular endothelium and smooth muscle cells [ 40 ]. Exposure to homocysteine, a well-documented risk factor for atherosclerosis and stroke [ 41 , 42 ], in endothelial cells can form the intermediate S-nitroso-homocysteine, a vasodilator implicated in reducing vascular tone and altering arteriole calcium levels [ 40 ] Collectively, these associations have identified a novel association with ZDHHC6 and implicate PI3K/Akt signaling in time to stroke and/or vascular event following stroke [ 43 , 44 ]. These findings could in part, help explain the ethnic disparities in stroke severity and recovery seen in African American patients; however, further functional analyses are needed to confirm the biological significance of our results.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation analyses identify an intronic ZDHHC6 locus associated with time to recurrent stroke in the Vitamin Intervention for Stroke Prevention (VISP) clinical trial

et al. 2021

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Aberrant DNA methylation profiles have been implicated in numerous cardiovascular diseases; however, few studies have investigated how these epigenetic modifications contribute to stroke recurrence. The aim of this study was to identify methylation loci associated with the time to recurrent cerebro- and cardiovascular events in individuals of European and African descent. DNA methylation profiles were generated for 180 individuals from the Vitamin Intervention for Stroke Prevention clinical trial using Illumina HumanMethylation 450K BeadChip microarrays, resulting in beta values for 470,871 autosomal CpG sites. Ethnicity-stratified survival analyses were performed using Cox Proportional Hazards regression models for associations between each methylation locus and the time to recurrent stroke or composite vascular event. Results were validated in the Vall d’Hebron University Hospital cohort from Barcelona, Spain. Network analyses of the methylation loci were generated using weighted gene coexpression network analysis. Primary analysis identified four significant loci, cg04059318, ch.2.81927627R, cg03584380, and cg24875416, associated with time to recurrent stroke. Secondary analysis identified three loci, cg00076998, cg16758041, and cg02365967, associated with time to composite vascular endpoint. Locus cg03584380, which is located in an intron of ZDHHC6, was replicated in the Vall d’Hebron University Hospital cohort. The results from this study implicate the degree of methylation at cg03584380 is associated with the time of recurrence for stroke or composite vascular events across two ethnically diverse groups. Furthermore, modules of loci were associated with clinical traits and blood biomarkers including previous number of strokes, prothrombin fragments 1 + 2, thrombomodulin, thrombin-antithrombin complex, triglyceride levels, and tissue plasminogen activator. Ultimately, these loci could serve as potential epigenetic biomarkers that could identify at-risk individuals in recurrence-prone populations.

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MiR-145 alleviates Hcy-induced VSMC proliferation, migration, and phenotypic switch through repression of the PI3K/Akt/mTOR pathway

Zhang

Wang

et al. 2020

Histochem Cell Biol

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Homocysteine ameliorates the endothelium-independent hypoxic vasoconstriction via the suppression of phosphatidylinositol 3-kinase/Akt pathway in porcine coronary arteries

Cited by 4 publications

References 39 publications

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

DNA methylation analyses identify an intronic ZDHHC6 locus associated with time to recurrent stroke in the Vitamin Intervention for Stroke Prevention (VISP) clinical trial

MiR-145 alleviates Hcy-induced VSMC proliferation, migration, and phenotypic switch through repression of the PI3K/Akt/mTOR pathway

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