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

Calpain activation contributes to hyperglycemia-induced endothelial dysfunction and apoptosis. This study was designed to investigate the role of calpain inhibition in improving diabetic erectile dysfunction (ED) in mice. Thirty-eight-week-old male C57BL/6J mice were divided into three groups: (1) nondiabetic control group, (2) diabetic mice + vehicle group, and (3) diabetic mice + MDL28170 (an inhibitor of calpain) group. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg−1 body weight for 5 consecutive days. Thirteen weeks later, diabetic mice were treated with MDL28170 or vehicle for 4 weeks. The erectile function was assessed by electrical stimulation of the cavernous nerve. Penile tissues were collected for measurement of calpain activity and the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining was used to evaluate apoptosis. Caspase-3 expression and activity were also measured to determine apoptosis. Our results showed that erectile function was enhanced by MDL28170 treatment in diabetic mice compared with the vehicle diabetic group. No differences in calpain-1 and calpain-2 expressions were observed among the three groups. However, calpain activity was increased in the diabetic group and reduced by MDL28170. The eNOS-NO-cGMP pathway was upregulated by MDL28170 treatment in diabetic mice. Additionally, MDL28170 could attenuate apoptosis and increase the endothelium and smooth muscle levels in corpus cavernosum. Inhibition of calpain could improve erectile function, probably by upregulating the eNOS-NO-cGMP pathway and reducing apoptosis.

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“… 9 10 The development of diabetic endothelial dysfunction is multifactorial, and calpain may play a critical role in this disorder. 11 …”

Section: Introductionmentioning

confidence: 99%

Calpain inhibition improves erectile function in diabetic mice via upregulating endothelial nitric oxide synthase expression and reducing apoptosis

Chen

Wang

et al. 2018

Asian J Androl

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Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

Korthuis

2018

Advances in Pharmacology

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Ischemia/reperfusion (I/R) induces leukocyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated dilatory responses (EDD) in upstream arterioles. A large body of evidence has implicated reactive oxygen species (ROS), adherent leukocytes, and proteases in postischemic EDD dysfunction in conduit arteries. However, arterioles represent the major site for the regulation of vascular resistance, but have received less attention with regard to the mechanisms underlying their reduced responsiveness to EDD stimuli in I/R. Even though leukocytes do not roll along, adhere to, or emigrate across arteriolar endothelium in postischemic intestine, recent work indicates that I/R-induced venular LECA is causally linked to EDD in arterioles. An emerging body of evidence supports the view that I/R-induced EDD in arterioles occurs by a mechanism that is triggered by LECA in postcapillary venules and involves the formation of signals in the interstitium elicited by the proteolytic activity of emigrated leukocytes. This activity releases matricryptins from or exposes matricryptic sites in the extracellular matrix (ECM) that interact with the integrin αvβ3 to induce mast cell chymase-dependent formation of angiotensin II (Ang II). Subsequent activation of NAD(P)H oxidase by Ang II leads to the formation of oxidants which inactivate NO, resulting in arteriolar EDD dysfunction. ROS generation also promotes eNOS uncoupling in the vascular wall, exacerbating impaired EDD responses. This work establishes new links between LECA in postcapillary venules, signals generated in the interstitium by emigrated leukocytes, mast cell degranulation, and impaired EDD in upstream arterioles. Given the importance of the endothelium in regulating vascular tone, these fundamentally important findings have enormous implications for our understanding of blood flow dysregulation in conditions characterized by I/R.

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

Cited by 2 publications

References 59 publications

Calpain inhibition improves erectile function in diabetic mice via upregulating endothelial nitric oxide synthase expression and reducing apoptosis

Calpain inhibition improves erectile function in diabetic mice via upregulating endothelial nitric oxide synthase expression and reducing apoptosis

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

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