New insights of µ-calpain in the pathogenesis of diabetic vascular injury.

Abstract

The prevalence of diabetes, the most common noncommunicable health condition, is increasing at an alarming rate. It is estimated that over the next 20 years, this condition will affect 400 million people, or ∼4.4% of the world’s population (1,2). Diabetes leads to a number of well-described long-term consequences involving multiple organ systems. Of these, cardiovascular disorders, end-stage renal disease, and blindness are of particular concern (3). Both type 1 and type 2 diabetes may be accompanied with circulatory anomalies that account for up to 80% of premature mortality and a heavy health care burden (3). Macrovascular circulatory abnormalities include angiopathy, atherosclerosis, increased vascular tone, arterial hypertension, and calcification in both medium and large arteries. Microvascular complications include retinopathy, nephropathy, and peripheral neuropathy (3,4). Regardless of the affected site, vascular injury shares some common histopathological features of endothelial and smooth muscle dysfunction. A plethora of theories have been postulated for diabetic vascular injury. They include increased flux through polyol and hexosamine pathways, activation of protein kinase C (PKC), oxidative stress, and accumulation of advanced glycation end products that lead to abnormal blood flow, apoptosis, hyperpermeability, and accumulation of extracellular matrix (3,5). Therapeutic strategies to address diabetic vascular injury include removing risk factors, such as hyperinsulinemia, hypertension, obesity, and hyperglycemia; blocking injurious mechanisms; and promoting protective processes, such as insulin-regulated genes, antioxidant or anti-inflammatory factors, or cell survival factors (5). Recent evidence supports an independent role for hyperhomocysteinemia (HHcy), or elevated levels of plasma homocysteine (Hcy), in the pathogenesis of vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, …