Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
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Query: UMLS:C0020473 (
hyperlipidemia
)
15,891
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Functional and structural changes in mitochondria are caused by the opening of the mitochondrial permeability transition pore (PTP) and by the mitochondrial generation of reactive oxygen species (ROS). These two processes are linked in a vicious cycle that has been extensively documented in ischemia/reperfusion injuries of the heart, and the same processes likely contribute to vascular pathology. For instance, the opening of the PTP causes cell death in isolated endothelial and vascular smooth muscle cells. Indeed, atherosclerosis is exacerbated when mitochondrial antioxidant defenses are hampered, but a decrease in mitochondrial ROS formation reduces atherogenesis. Determining the exact location of ROS generation in mitochondria is a relevant and still unanswered question. The respiratory chain is generally believed to be a main site of ROS formation. However, several other mitochondrial components likely contribute to ROS generation. Recent reports highlight the relevance of monoamine oxidases (MAO) and
p66
(Shc). For example, the absence of
p66
(Shc) in hypercholesterolemic mice has been reported to reduce the occurrence of foam cells and early atherogenic lesions. On the other hand, MAO inhibition has been shown to reduce oxidative stress in many cell types eliciting significant protection from myocardial ischemia. In conclusion, evidence will be presented to demonstrate that (i) mitochondria are major sites of ROS formation; (ii) an increase in mitochondrial ROS formation and/or a decrease in mitochondrial antioxidant defenses exacerbate atherosclerosis; and (iii) mitochondrial dysfunction is likely a relevant mechanism underlying several risk factors (i.e., diabetes,
hyperlipidemia
, hypertension) associated with atherosclerosis.
...
PMID:Mitochondria and vascular pathology. 1930
Impaired activated protein C (aPC) generation is associated with atherosclerosis and diabetes mellitus. Diabetes-associated atherosclerosis is characterized by the hyperglycaemic memory, e.g., failure of disease improvement despite attenuation of hyperglycaemia. Therapies reversing the hyperglycaemic memory are lacking. Here we demonstrate that hyperglycaemia, but not
hyperlipidaemia
, induces the redox-regulator
p66
Shc
and reactive oxygen species (ROS) in macrophages.
p66
Shc
expression, ROS generation, and a pro-atherogenic phenotype are sustained despite restoring normoglycemic conditions. Inhibition of
p66
Shc
abolishes this sustained pro-atherogenic phenotype, identifying
p66
Shc
-dependent ROS in macrophages as a key mechanism conveying the hyperglycaemic memory. The
p66
Shc
-associated hyperglycaemic memory can be reversed by aPC via protease-activated receptor-1 signalling. aPC reverses glucose-induced CpG hypomethylation within the
p66
Shc
promoter by induction of the DNA methyltransferase-1 (DNMT1). Thus, epigenetically sustained
p66
Shc
expression in plaque macrophages drives the hyperglycaemic memory, which-however-can be reversed by aPC. This establishes that reversal of the hyperglycaemic memory in diabetic atherosclerosis is feasible.
...
PMID:Activated protein C reverses epigenetically sustained p66
Shc
expression in plaque-associated macrophages in diabetes. 3027 84
