ArticleDiabetes2015
Hyperhomocysteinemia and hyperglycemia induce and potentiate endothelial dysfunction via μ-calpain activation.
Article in Diabetes, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 2 of them syntheses that pooled it.
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Who cites it
48 citing papers in PubMed, 2 syntheses or guidelines pooled it, 80 citations in OpenAlex.
- Effects of curcumin supplementation on homocysteine levels: a systematic review and meta-analysis of randomized controlled trials.Frontiers in pharmacology · 2026Pooled it
- Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer's disease.Alzheimer's research & therapy · 2023Pooled it
- Homocysteine and mitophagy in diabetic retinopathy: unraveling the underlying molecular crosstalk.Endocrine · 2026Review
- Hyperglycemia-Induced Endothelial Dysfunction: From Classical Pathogenetic Mechanisms to Emerging Insights into ACE2 Protective Action.International journal of molecular sciences · 2026Review
- Exerkines in diabetic retinopathy: from mechanisms to therapeutic prospects.Frontiers in endocrinology · 2026Review
- Muscle-specific miR-499-5p delivered by small extracellular vesicles impairs endothelial function and ischemic hindlimb recovery in diabetic mice.Cardiovascular diabetology · 2025Article
- Repeated platelet-rich plasma injections improve erectile dysfunction in a rat model of hyperhomocysteinemia.Asian journal of andrology · 2024Article
- Ribosomal modification protein rimK-like family member A activates betaine-homocysteine S-methyltransferase 1 to ameliorate hepatic steatosis.Signal transduction and targeted therapy · 2024Article
- Mitochondrial quality control in human health and disease.Military Medical Research · 2024Review
- Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.Redox biology · 2023Article
- The Regulatory Effect of Phytochemicals on Chronic Diseases by Targeting Nrf2-ARE Signaling Pathway.Antioxidants (Basel, Switzerland) · 2023Review
- Ginsenoside Rg1 ameliorates chronic intermittent hypoxia-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway.Journal of ginseng research · 2023Article
- Prevalence of hyperhomocysteinemia (HHcy) and its major determinants among hypertensive patients over 35 years of age.European journal of clinical nutrition · 2022Article
- Reduced Levels of HAntioxidants (Basel, Switzerland) · 2022Article
- Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis.Frontiers in cardiovascular medicine · 2022Review
- Individuals with Bipolar Disorder Have a Higher Level of Homocysteine Than Major Depressive Disorder: A Retrospective Chart Review and Observational Study.Neuropsychiatric disease and treatment · 2022Article
- Molecular processes mediating hyperhomocysteinemia-induced metabolic reprogramming, redox regulation and growth inhibition in endothelial cells.Redox biology · 2021Article
- Thrombosis associated withExperimental and therapeutic medicine · 2021Review
- Homocysteine predicts vascular target organ damage in hypertension and may serve as guidance for first-line antihypertensive therapy.Journal of clinical hypertension (Greenwich, Conn.) · 2021Article
- Associations between urinary 6-sulfatoxymelatonin excretion and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes.Journal of diabetes investigation · 2021Article
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12 authors at 1 institution in 1 country.
Funding
Abstract
Plasma homocysteine (Hcy) levels are positively correlated with cardiovascular mortality in diabetes. However, the joint effect of hyperhomocysteinemia (HHcy) and hyperglycemia (HG) on endothelial dysfunction (ED) and the underlying mechanisms have not been studied. Mild (22 µmol/L) and moderate (88 µmol/L) HHcy were induced in cystathionine β-synthase wild-type (Cbs(+/+)) and heterozygous-deficient (Cbs(-/+)) mice by a high-methionine (HM) diet. HG was induced by consecutive injection of streptozotocin. We found that HG worsened HHcy and elevated Hcy levels to 53 and 173 µmol/L in Cbs(+/+) and Cbs(-/+) mice fed an HM diet, respectively. Both mild and moderate HHcy aggravated HG-impaired endothelium-dependent vascular relaxation to acetylcholine, which was completely abolished by endothelial nitric oxide synthase (eNOS) inhibitor N(G)-nitro-L-arginine methyl ester. HHcy potentiated HG-induced calpain activation in aortic endothelial cells isolated from Cbs mice. Calpain inhibitors rescued HHcy- and HHcy/HG-induced ED in vivo and ex vivo. Moderate HHcy- and HG-induced μ-calpain activation was potentiated by a combination of HHcy and HG in the mouse aorta. μ-Calpain small interfering RNA (μ-calpsiRNA) prevented HHcy/HG-induced ED in the mouse aorta and calpain activation in human aortic endothelial cells (HAECs) treated with DL-Hcy (500 µmol/L) and d-glucose (25 mmol) for 48 h. In addition, HHcy accelerated HG-induced superoxide production as determined by dihydroethidium and 3-nitrotyrosin staining and urinary 8-isoprostane/creatinine assay. Antioxidants rescued HHcy/HG-induced ED in mouse aortas and calpain activation in cultured HAECs. Finally, HHcy potentiated HG-suppressed nitric oxide production and eNOS activity in HAECs, which were prevented by calpain inhibitors or μ-calpsiRNA. HHcy aggravated HG-increased phosphorylation of eNOS at threonine 497/495 (eNOS-pThr497/495) in the mouse aorta and HAECs. HHcy/HG-induced eNOS-pThr497/495 was reversed by µ-calpsiRNA and adenoviral transduced dominant negative protein kinase C (PKC)β2 in HAECs. HHcy and HG induced ED, which was potentiated by the combination of HHcy and HG via μ-calpain/PKCβ2 activation-induced eNOS-pThr497/495 and eNOS inactivation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.