Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin-related peptides

Abstract

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man.

Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells

“…Indeed, there is some evidence that ketoconazole and prednisone, which reduce circulating testosterone levels, can help prevent recurrent ischemic priapism (51), and, potentially, some of their physiological activity could be mediated through decreased opiorphin expression. In addition, as described above, opiorphin can be detected in the bloodstream and saliva of patients (52), and in rats, levels of vcsa1 expression in corporal tissue are reflected by sialorphin levels in the blood (47). Therefore, opiorphin levels in the blood are potentially a useful biomarker for SCD‐related priapic crisis.…”

“…The mechanism described here, where hypoxic upregulation of sialorphin results in transcriptional activation of Hif‐1a and A2BR, may be restricted to CSM tissue, which under normal physiological conditions expresses high levels of vcsa1 relative to other tissues (15‐18). However, we have previously demonstrated that changes in expression of vcsa1 in rat corporal tissue are reflected by circulating levels of sialorphin in the blood (47). We have demonstrated that gene transfer of vectors into rat corporal tissue can increase sialorphin levels in the blood of diabetic rats, and the increased levels of sialorphin in blood are associated with reduced systemic blood pressure.…”

Autonomic Regulation of Anti-Inflammatory Activities from Salivary Glands

“…erectile function [59,[61][62][63][64], through relaxation of corporal smooth muscle tissue through a GPCR (G-protein coupled receptor) mechanism [62,65].…”

Current perspectives in coronary microvascular dysfunction

“…This workflow is associated with procedural risks, reduction of patient quality of life, exposure to ionizing radiation, and high costs . Few studies have specifically addressed CMD treatment, despite the fact that several drugs proved effective in restoring microvascular function in animal models of MD . This in part reflects the absence of a single tool for the diagnosis of CMD and to monitor effects of therapy.…”