Abstract
Diabetes is one of the most prevalent metabolic disorders. In diabetes, incidence of coronary artery diseases and peripheral vascular diseases is increased 2- to 4-fold and 10-fold, respectively, compared to healthy individuals. In spite of extensive studies, the underlying mechanisms of endothelial dysfunction (ED), an early event in the development of vascular diseases, remain incompletely understood in diabetes. This mini-review discusses the role and signaling pathways of calpains - a family of Ca2+-sensitive intracellular proteases in nitric oxide (NO)-mediated ED in diabetes. We conclude that activation of calpains, especially μ-calpain, plays an important role in the pathogenesis of NO-mediated ED and inflammatory responses in diabetes which is mainly via endothelial Nitric Oxide Synthase (eNOS) inactivation/degradation in macro- and micro-vasculature. We review existing literature demonstrating that hyperhomocysteinemia, elevated plasma homocysteine level, potentiates hyperglycemia-induced ED via μ-calpain/PKCβ2 activation-induced eNOS-pThr497/495 and eNOS inactivation. μ-calpain may be a critical therapeutic target for NO-mediated ED in diabetes.
Highlights
Diabetes, one of the most prevalent metabolic disorders, is estimated to affect 400 million or 4.4% of population worldwide in the 20 years [1,2]
We demonstrated that HHcy potentiated hyperglycemia-induced Endothelial dysfunction (ED) via μ-calpain/PKCβ2 activation-mediated endothelial Nitric Oxide Synthase (eNOS)-pThr49, eNOS inactivation and nitric oxide (NO) reduction [15]
We have found that EDHFmediated endothelium-dependent vascular relaxation was impaired in the mesenteric artery of diabetic Goto-Kakizaki rats and this relaxation was aggravated by high-salt diet [59]
Summary
One of the most prevalent metabolic disorders, is estimated to affect 400 million or 4.4% of population worldwide in the 20 years [1,2]. Different calpain seem to serve unique roles in the pathogenesis of diabetes, discovery of selective calpain inhibitors are critically for the treatment of cardiovascular complications in diabetes Both μ- and m-calpain are expressed in vascular cells, including ECs and vascular smooth muscle cells (VSMCs). HHcy induces the translocation of active μ-calpain from cytosol to mitochondria, leading to increased intramitochondrial oxidative stress in cultured rat heart microvascular endothelial cells [16]. We believe that our findings will provide fundamental insights for the prevention and treatment of cardiovascular diseases in patients with diabetes and HHcy. In response to pathophysiological stimulation, the endothelium maintains vascular hemostasis by releasing vasodilator substances, such as nitric oxide (NO), prostacyclin (PGI2) and endotheliumderived hyperpolarizing factor (EDHF), and vasoconstrictor substances, such as angiotension II, endothelin-1, thromboxane A, and prostaglandin H2 [5,6].
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