Important roles and mechanisms of novel calcium signaling in diabetes-induced vascular dementia

Title : Important roles and mechanisms of novel calcium signaling in diabetes-induced vascular dementia

Abstract:

Vascular dementia is a common neurodegenerative disease. This dementia is caused by cerebral blood vessel dysfunctions. It has high morbidity and mortality. Diabetes is a leading factor in the development of this dementia. However, the essential roles, mechanisms and consequences of vascular dementia are still largely unknown. Moreover, the current treatments for vascular dementia are neither very specific nor effective. Dysfunctions of cerebral arteries (CAs) may cause blood hypoperfusion to the brain and then makes an important contribution in the initiation and progress of vascular dementia. Perfusion of CAs is predominantly generated and controlled by contraction and relaxation of smooth muscle cells (SMCs). These two cellular processes are fundamentally produced and regulated by cell calcium signaling. The cell calcium signaling is primarily determined by ion channels on the plasma membrane and sarcoplasmic reticulum (SR) membrane. Therefore, we have started to explore whether and which ion channels might be essential for diabetes-evoked vascular dementia. Consistent with previous reports by us and other investigators, we have found that intraperitoneal injection of streptozotocin caused a large increase in blood glucose, leading to diabetes in mice. A series of our studies have also discovered that the diabetic mice had declined cognition, impaired memory, and increased anxiety, thereby exhibiting significant vascular dementia. This diabetic vascular dementia might occur due to cerebral vasoconstriction and subsequent blood hypoperfusion, as revealed by Laser Speckle Imaging System. Diabetic cerebral vasoconstriction could result from increased intracellular calcium concentration ([Ca²⁺]_i) in CASMCs. Increased [Ca²⁺]_i was attributed to the augmented Ca²⁺ release from the SR, the major intracellular Ca²⁺ store, which followed the hyperfunctional activity of type-2 ryanodine receptor (RyR2), the calcium release channel on the SR in CASMCs. Biochemical and genetic experiments indicated that the hyperfunction of RyR2 channel was a result of dissociation of FK506 binding protein 12.6 (FKBP12.6), an endogenous channel stabilizer (or inhibitor). In conclusion, our findings provide the first evidence that RyR2/FKBP12.6 dissociation exerts a novel essential role in the development of diabetes-caused vascular dementia; presumably, specific pharmacological and genetic inhibition of RyR2 and/or stabilization of FKBP12.6 in vascular SMCs may become specific and effective treatment options for diabetes-induced vascular dementia.

Biography:

Dr. Yong-Xiao Wang has been a Full Professor in Department of Molecular and Cellular Physiology at Albany Medical College since 2006. Dr. Wang obtained his MD at Wannan Medical University, PhD at Fourth Military Medical University, and postdoctoral training at Technology University of Munich and University of Pennsylvania. He has made many important findings using complementary molecular, biochemical, physiological, and genetic approaches at the molecular, organelle, cellular, tissue and organism levels in animals and human samples, had numerous publications in Nature Commun (impact factor: 14.290), Antioxid Redox Signal (8.209), Proc Natl Acad Sci USA (9.432), Nature (34.480), Circ Res (9.214), and other highly peer-reviewed journals and academic books, and served as the editorial board member and/or section editor as well as the executive committee member and/or subcommittee chair for professional societies.