Pharmacological pleiotropic effects on the vascular function and blood flow of arteriovenous fistula in diabetes

Abstract

Diabetes mellitus the most common cause of end-stage renal disease (ESRD) in Taiwan is an independent risk factor of reduced blood flow in arteriovenous (AV) fistula However there is currently limited therapeutic strategy to prevent the loss of primary patency and to improve durability of AV access among diabetes This PhD thesis aimed to identify the mechanism of AV fistula dysfunction induced by hyperglycemia Insulin-dependent diabetes was induced in Sprague-Dawley rats by a single injection of streptozotocin (60 mg-1·kg-1) One week after induction of diabetes an AV fistula was created in abdominal aorta and the adjacent inferior vena cava of anesthetized rats Rats were allocated to control or rosuvastatin-treated groups which receive placebo or rosuvastatin (15 mg·kg-1·day-1) in chow for 2 weeks It was then acknowledged that the generation of pleiotropic effects including anti-inflammation anti-oxidant and EPC mobilization could be essential pleiotropic effects to improve AV fistula function Exendin-4 (Ex4) a glucagon like peptide-1 analogue presented similar pleiotropic effects as statins To testify the hypothesis those diabetic rats received intraperitoneal vehicle or Ex4 (0 5 μg·kg-1·day-1) before creation of AV fistula The aortic limb of AV fistula was analyzed on day 14 postoperatively Ex4 was found to present anti-inflammatory effects in aorta tissue and mobilized circulating EPCs diabetic rats However Ex4 failed to attenuate abundances of phosphorylated p47phox a major subunit of NADPH oxidase and did not improve AV fistula blood flow These important findings indicated the importance of anti-oxidative effects of rosuvastatin in the AV fistula of hyperglycemic rats The cyclic guanosine monophosphate (cGMP) was then restored in rosuvastatin treated rats which improve vascular relaxation and fistula blood flow These findings were pivotal to the following clinical studies in my thesis Before initiating the clinical trial a pilot study is conducted to survey the incidence of AV fistula failure among ESRD subjects with diabetes This prospective cohort study revealed a primary failure rate of 24 1% among those who received AV fistula surgery In addition there was a positive correlation between fistula wall stress and circulating EPC numbers The mobilization of circulating EPCs was statistically significant among patients who developed a compromised radiocephalic fistula within 90 days postoperatively A double blind randomized control trial was then conducted in ESRD subjects with diabetes On preparing this PhD thesis manuscript a total of 53 cases were included in this trial and we expected promising findings to improve the life quality of this patient group In summary this PhD project identified that rosuvastatin presented non-lipid lowering pleiotropic effects in AV fistula of diabetes Rosuvastatin restored AV fistula blood flow and vascular function mainly through anti-oxidative mechanism which attenuated the uncoupling of eNOS and promoted the propagation of NO-cGMP pathway The beneficial effect of rosuvastatin over AV fistula is clinically applicable and is supposed to be evident from the ongoing clinical trial

Date of Award	2016 Nov 9
Original language	English
Supervisor	Chwan-Yau Luo (Supervisor)