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μ-Calpain as a Novel Target for Impairment of Nitric Oxide-Mediated Vascular Relaxation in Diabetes: A Mini Review.

Kishore R, Benedict C, Cheng Z - J Mol Genet Med (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Medicine and Department of Pharmacology, Temple University School of Medicine, USA.

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 Ca(2+)-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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the risk factors for calpains activation in the ECs. Ang II, angiotensin II; LDL, low density lipoprotein; VEGF, vascular endothelial growth factor.
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Figure 1: Schematic representation of the risk factors for calpains activation in the ECs. Ang II, angiotensin II; LDL, low density lipoprotein; VEGF, vascular endothelial growth factor.

Mentions: Both μ- and m-calpain are expressed in vascular cells, including ECs and vascular smooth muscle cells (VSMCs). The role of calpains in regulation of EC functional properties has been extensively examined. Calpains act on ECs, thus maintaining vascular physiological integrity [25–27]. Whereas, over activation of calpains appears to play an important role in pathogenesis of angiogenesis [11,28], ED [9,10,24,29] and wound healing [30]. Many factors have been suggested to induce calpains activation in ECs (Figure 1). Vascular endothelial growth factor increased μ-calpain activity in both human microvascular and bovine aortic endothelial cells [11,31]. Shear stress increased μ-calpain activity in mouse aortic and human umbilical vein endothelial cells (HUVECs) [11,26,32]. Angiotensin II induces μ-calpain activation in the endothelia cells of mouse postcapillary venules [29]. Hypoxia induces calpains activation in porcine pulmonary artery ECs [33]. Moreover, oxidized LDL enhanced μ-calpain activity in HUVECs [34]. Antioxidants reduced μ-calpain but not m-calpain activity in mouse pulmonary microvascular endothelial cells. High glucose increases μ-calpain activity in HVECs [35] and mouse micro- and macro-vascular ECs [9,10,15,24].


μ-Calpain as a Novel Target for Impairment of Nitric Oxide-Mediated Vascular Relaxation in Diabetes: A Mini Review.

Kishore R, Benedict C, Cheng Z - J Mol Genet Med (2015)

Schematic representation of the risk factors for calpains activation in the ECs. Ang II, angiotensin II; LDL, low density lipoprotein; VEGF, vascular endothelial growth factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482122&req=5

Figure 1: Schematic representation of the risk factors for calpains activation in the ECs. Ang II, angiotensin II; LDL, low density lipoprotein; VEGF, vascular endothelial growth factor.
Mentions: Both μ- and m-calpain are expressed in vascular cells, including ECs and vascular smooth muscle cells (VSMCs). The role of calpains in regulation of EC functional properties has been extensively examined. Calpains act on ECs, thus maintaining vascular physiological integrity [25–27]. Whereas, over activation of calpains appears to play an important role in pathogenesis of angiogenesis [11,28], ED [9,10,24,29] and wound healing [30]. Many factors have been suggested to induce calpains activation in ECs (Figure 1). Vascular endothelial growth factor increased μ-calpain activity in both human microvascular and bovine aortic endothelial cells [11,31]. Shear stress increased μ-calpain activity in mouse aortic and human umbilical vein endothelial cells (HUVECs) [11,26,32]. Angiotensin II induces μ-calpain activation in the endothelia cells of mouse postcapillary venules [29]. Hypoxia induces calpains activation in porcine pulmonary artery ECs [33]. Moreover, oxidized LDL enhanced μ-calpain activity in HUVECs [34]. Antioxidants reduced μ-calpain but not m-calpain activity in mouse pulmonary microvascular endothelial cells. High glucose increases μ-calpain activity in HVECs [35] and mouse micro- and macro-vascular ECs [9,10,15,24].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Medicine and Department of Pharmacology, Temple University School of Medicine, USA.

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 Ca(2+)-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.

No MeSH data available.


Related in: MedlinePlus