title: Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology.
abstract: Events responsible for cerebrovascular disease in diabetes are not fully understood. Pericyte loss is an early event that leads to endothelial cell death, microaneurysms, and cognitive impairment. A biochemical mechanism underlying pericyte loss is rapid respiration (oxidative metabolism of glucose). This escalation in respiration results from free influx of glucose into insulin-insensitive tissues in the face of high glucose levels in the blood. Rapid respiration generates superoxide, the precursor to all reactive oxygen species (ROS), and results in pericyte death. Respiration is regulated by carbonic anhydrases (CAs) VA and VB, the two isozymes expressed in mitochondria, and their pharmacologic inhibition with topiramate reduces respiration, ROS, and pericyte death. Topiramate inhibits both isozymes; therefore, in the earlier studies, their individual roles were not discerned. In a recent genetic study, we showed that mitochondrial CA VA plays a significant role in regulation of reactive oxygen species and pericyte death. The role of CA VB was not addressed. In this report, genetic knockdown and overexpression studies confirm that mitochondrial CA VA regulates respiration in pericytes, whereas mitochondrial CA VB does not contribute significantly. Identification of mitochondrial CA VA as a sole regulator of respiration provides a specific target to develop new drugs with fewer side effects that may be better tolerated and can protect the brain from diabetic injury. Since similar events occur in the capillary beds of other insulin-insensitive tissues such as the eye and kidney, these drugs may also slow the onset and progression of diabetic disease in these tissues.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Saint Louis University School of Medicine, Edward A. Doisy Research Center, 1100 South Grand Blvd, DRC 354, Saint Louis, MO 63104, USA.
authors.forename: Tulin O
authors.initials: TO
authors.lastname: Price
authors.affiliation: Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Saint Louis University School of Medicine, Edward A. Doisy Research Center, 1100 South Grand Blvd, DRC 354, Saint Louis, MO 63104, USA. Electronic address: shahgn@slu.edu.
authors.forename: Gul N
authors.initials: GN
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D024404:Carbonic Anhydrase V / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D002561:Cerebrovascular Disorders / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020286:Pericytes / Q000201:enzymology* / Q000473:pathology
chemical_list: D024101:Mitochondrial Proteins; D024404:Carbonic Anhydrase V; C581910:Car5A protein, mouse
keywords: Apoptosis; Brain peicytes; Diabetes; Mitochondrial carbonic anhydrases; Reactive oxygen species