Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in...

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Diabetes mellitus is a significant risk factor for cardiovascular disease, with underlying molecular mechanisms requiring elucidation.
• Prolyl-isomerase Pin1 is a key regulator of protein function and cellular homeostasis.
• The specific role of Pin1 in the pathogenesis of diabetes-induced vascular complications is not well understood.

Purpose of the Study:

• To investigate the role of Prolyl-isomerase Pin1 in the development of vascular disease associated with diabetes.
• To elucidate the molecular mechanisms by which Pin1 contributes to diabetes-induced endothelial dysfunction and inflammation.

Main Methods:

• Experiments were conducted using human aortic endothelial cells (HAECs) exposed to high glucose conditions.
• Studies involved gene silencing of Pin1, assessment of mitochondrial translocation of p66(Shc), nitric oxide (NO) availability, and nuclear translocation of NF-κB p65.
• Diabetic Pin1 knockout mice were utilized to evaluate in vivo effects on mitochondrial oxidative stress, endothelial function, and vascular inflammation.
• Peripheral blood monocytes from diabetic patients and healthy controls were analyzed for Pin1 expression and activity.

Main Results:

• High glucose induced Pin1 upregulation in HAECs, leading to p66(Shc) mitochondrial translocation, oxidative stress, and endothelial nitric oxide synthase (eNOS) dysregulation.
• Pin1 mediated hyperglycaemia-induced NF-κB p65 nuclear translocation, increasing expression of inflammatory markers (VCAM-1, ICAM-1, MCP-1).
• Pin1 gene silencing in HAECs reversed these detrimental effects, while diabetic Pin1(-/-) mice showed protection against vascular damage.
• Elevated Pin1 expression and activity were observed in monocytes from diabetic patients, correlating with impaired vascular function and increased markers of oxidative stress and inflammation.

Conclusions:

• Pin1 plays a critical role in driving diabetic vascular disease through mechanisms involving mitochondrial oxidative stress, eNOS dysregulation, and NF-κB-mediated inflammation.
• These findings offer novel molecular insights into the pathogenesis of diabetic vascular complications.
• Targeting Pin1 presents a potential therapeutic strategy for managing diabetes-related cardiovascular diseases.