Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Paneni, F; Mocharla, P; Akhmedov, A; Costantino, S; Osto, E; Volpe, M; Lüscher, TF; Cosentino, F.
Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes.
Circ Res. 2012; 111(3):278-89
Doi: 10.1161/CIRCRESAHA.112.266593
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Osto Elena
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- Abstract:
- RATIONALE: Hyperglycemic memory may explain why intensive glucose control has failed to improve cardiovascular outcomes in patients with diabetes. Indeed, hyperglycemia promotes vascular dysfunction even after glucose normalization. However, the molecular mechanisms of this phenomenon remain to be elucidated. OBJECTIVE: The present study investigated the role of mitochondrial adaptor p66(Shc) in this setting. METHODS AND RESULTS: In human aortic endothelial cells (HAECs) exposed to high glucose and aortas of diabetic mice, activation of p66(Shc) by protein kinase C βII (PKCβII) persisted after returning to normoglycemia. Persistent p66(Shc) upregulation and mitochondrial translocation were associated with continued reactive oxygen species (ROS) production, reduced nitric oxide bioavailability, and apoptosis. We show that p66(Shc) gene overexpression was epigenetically regulated by promoter CpG hypomethylation and general control nonderepressible 5-induced histone 3 acetylation. Furthermore, p66(Shc)-derived ROS production maintained PKCβII upregulation and PKCβII-dependent inhibitory phosphorylation of endothelial nitric oxide synthase at Thr-495, leading to a detrimental vicious cycle despite restoration of normoglycemia. Moreover, p66(Shc) activation accounted for the persistent elevation of the advanced glycated end product precursor methylglyoxal. In vitro and in vivo gene silencing of p66(Shc), performed at the time of glucose normalization, blunted ROS production, restored endothelium-dependent vasorelaxation, and attenuated apoptosis by limiting cytochrome c release, caspase 3 activity, and cleavage of poly (ADP-ribose) polymerase. CONCLUSIONS: p66(Shc) is the key effector driving vascular hyperglycemic memory in diabetes. Our study provides molecular insights for the progression of diabetic vascular complications despite glycemic control and may help to define novel therapeutic targets.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Cells, Cultured - administration & dosage
- Diabetes Mellitus, Experimental - genetics, metabolism, pathology
- Gene Knockdown Techniques - methods
- Gene Silencing - physiology
- Glucose - pharmacology
- Humans - administration & dosage
- Hyperglycemia - genetics, pathology, physiopathology
- Male - administration & dosage
- Mice - administration & dosage
- Mice, 129 Strain - administration & dosage
- Mitochondria - drug effects, pathology
- Organ Culture Techniques - administration & dosage
- Shc Signaling Adaptor Proteins - deficiency, genetics, physiology
- Src Homology 2 Domain-Containing, Transforming Protein 1 - administration & dosage
- Find related publications in this database (Keywords)
- vascular disease
- diabetes mellitus
- free radicals
- endothelium