Diabetes mellitus is a debilitating metabolic disorder affecting millions of people worldwide. One of the hallmark symptoms of diabetes is hyperglycemia (elevated blood glucose levels; HG). At least 60% of the diabetic patient develop hypertension and become susceptible to both macro and microvascular complications, including stroke. HG is associated with excessive vascular tone and dysfunction of the blood vessels. Recently, we demonstrated that activation of protein kinase A (PKA) leads to phosphorylation and potentiation of L‐type Ca V 1.2 channels in vascular smooth muscle resulting is increased vasoconstriction during HG. A fundamental gap in knowledge that remains unexplored is the upstream mechanisms underlying PKA activation. Here, we describe for the first time a critical role for local cAMP production by adenylyl cyclase (AC) isoform 5, upstream of PKA, in regulation and potentiation of Ca V 1.2 channels leading to vasoconstriction during HG. Consistent with this, membrane‐targeted fluorescence resonance energy transfer (FRET) biosensor for cAMP revealed a small but significant increase in cAMP production by HG, in agreement with local cAMP production. Treatment with forskolin (global cAMP activator) resulted in a significantly larger cAMP signal, aligned with cell wide global cAMP increase. In the presence of the specific AC5 and AC6 inhibitor 2,5,DDA or in vascular smooth muscle from AC5−/− mice, the HG‐induced cAMP increase was abolished. Yet, the forskolin‐induced global increase in cAMP production remained intact. Electrophysiology and pressure‐myography experiments demonstrated that the 2,5 DDA compound and genetic ablation of AC5, but not AC6, abrogated the increased in L‐type Ca V 1.2 channel activity and vasoconstriction in response to HG. Super‐resolution microscopy and proximity ligation assay confirmed close association between AC5 and L‐type Ca V 1.2 channels. Taken together, these finding demonstrate a novel role of local AC5 signaling in HG‐induced vasoconstriction due to increased Ca V 1.2 activity leading to vasoconstriction during diabetic hyperglycemia. Support or Funding Information NIH R01HL098200, R01HL121059 and NIH T32‐HL086350 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Introduction: Dialysis patients have a higher rate of HCV infection.2 This study was carried out to find out the prevalence of HCV infection in patients on chronic haemodialysis and to identify the risk factors for HCV transmission in this patient group. Methods: This prospective cross sectional study was carried out in the haemodialysis units and the department of Gastrointestinal, Hepatobiliary and pancreatic disorders (GHPD) of BIRDEM hospital, during the period of March 2006 to March 2007. A total of 72 end stage renal disease patients of both sexes and all ages on maintenance heamodialysis for more than three months were enrolled. A pre-designed questionnaire comprising demographic, dialysis-specific, medical history and life style variables was filled up. Predialysis five (5) ml blood were taken from the arterial channel for anti-HCV (ELISA) test. P-value <0.05 was considered as significant. Results: The prevalence of HCV infection in patients on chronic haemodialysis was 23.6%. There was no statistical significance (p=0.133ns) between anti-HCV positivity and age and sex distribution. The association between HCV status and the total number of units of blood transfused, mean duration of haemodialysis and life-style risk factors for HCV transmission were statistically significant. Conclusion: In our study, the prevalence of HCV infection in patients on chronic haemodialysis was 23.6%. The haemodialysis patients in our dialysis unit have an infection rate 8-12 fold more than general population. The association between the total number of units of blood transfused, mean duration of haemodialysis, and presence of one or more risk factors and HCV positivity were statistically significant. J. Dhaka National Med. Coll. Hos. 2014;20(01): 9-14
