The cardiovascular biology of hydrogen sulphide

ROLE OF HYDROGEN SULPHIDE IN THE STREPTOZOTOCIN DIABETIC RAT – EFFECTS ON INSULIN RELEASE AND THE DIABETIC VASCULATURE MUHAMMED YUSUF ALI (B. Sc. (Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY NATIONAL UNIVERSITY OF SINGAPORE 2007 Acknowledgements I am immensely grateful to my supervisor Professor Philip K. Moore for all the time spent in helping and mentoring me through the course of my PhD endeavor. Sincere gratitude also goes out the entire Pharmacology and Cardiovascular Research Group for giving me the freedom to express my thoughts and ideas and for the guidance on the use of various equipments in the laboratory. I especially would like to thank all the Laboratory Technicians in the Pharmacology and Biochemistry departments for all their tireless help and sacrifice in making this thesis a reality. Many thanks go to the Thesis Advisory Committee (Associate Professor Madhav Bhatia, Associate Professor Benny Tan and Associate Professor Ed Manser) for their time and guidance during the course of my study. I thank Assistant Professor Loh Chian-Ming and his lab for generosity with the CBS expression plasmid. I am also grateful to Ms Angeline Goh for her assistance and advice with respect to the format of my thesis. I Table of Contents Acknowledgements I Table of Contents II Summary . VIII List of Figures . X List of Tables XIII List of publications .XIV Introduction 1.1 An overview of diabetes mellitus 1.2 Prevalence of diabetes mellitus 1.3 Release of insulin by pancreatic β-cells .2 1.4 Importance of insulin in diabetes mellitus .6 1.5 Diabetes-associated cardiovascular complications 1.6 Role of the vascular endothelium in maintaining blood pressure 10 1.7 Loss of vascular endothelium function in diabetes 13 1.8 Mechanisms of endothelial dysfunction in diabetes 14 1.9 Brief history of H2S-related effects in mammals .20 1.10 Endogenous H2S production in mammals .21 1.11 The importance of H2S-producing enzymes 22 1.12 Inhibitors of CBS or CSE activity .24 1.13 The biochemistry of H2S 25 1.14 Metabolism of H2S in mammals 25 1.15 Endogenous H2S produced in the brain and its related effects 27 1.16 Endogenous H2S produced in vascular tissues 28 1.17 H2S in pathophysiology .30 II 1.18 H2S in cardiovascular disease 32 1.19 H2S in inflammation 34 1.20 Other biological H2S effects 36 1.21 Type I diabetes and the streptozotocin-diabetic rat .39 Methods and Materials .41 2.1 Methods 41 2.1.1 Induction of diabetes and drug treatment of animals .41 2.1.2 Treatment of animals with insulin .42 2.1.3 Treatment of animals with metformin .42 2.1.4 Treatment of animals with propargylglycine (PAG) .43 2.1.5 Collection of plasma and tissue samples .44 2.1.6 Measurement of plasma glucose 44 2.1.7 Measurement of plasma insulin .45 2.1.8 Measurement of plasma glucagon .45 2.1.9 Measurement of plasma nitrate/nitrite (NOx) 46 2.1.10 Measurement of plasma amylase .47 2.1.11 Assay of plasma H2S concentration and tissue H2S synthesis .47 2.1.12 Reverse transcription polymerase chain reaction (RT-PCR) analysis of liver and kidney CBS and CSE mRNA .48 2.1.13 HIT-T15 cell culture 50 2.1.14 Cellular ATP, GSH and cell viability assay .51 2.1.15 Protein quantification .52 2.1.16 Cell transfection and immunoblotting .52 2.1.17 K+, Ca2+ and membrane polarity determination .53 2.1.18 Measurement of rat aorta contractility .54 III 2.1.19 Measurement of rat blood pressure 56 2.1.20 Statistics .56 2.2 Materials 57 2.2.1 Drugs and Chemicals .57 2.2.2 Materials and Equipment .58 Endogenous H2S production in the streptozotocin-induced diabetic rat .60 3.1 Introduction 60 3.2 Results 61 3.2.1 Changes in plasma glucose, rat weight and plasma insulin in streptozotocin-treated rats 61 3.2.2 Changes in H2S levels and biosynthesis in streptozotocin-induced diabetic rats. .62 3.2.3 Effect of insulin and metformin on diabetic rat weight, plasma glucose and plasma insulin 63 Changes in H2S levels and biosynthesis in streptozotocin-induced 3.2.4 diabetic rats treated with insulin and metformin 66 3.2.5 Changes in CBS and CSE mRNA expression levels in streptozotocininduced diabetes .70 3.2.6 Changes in nitrate & nitrite levels in streptozotocin-diabetic animals treated with insulin or metformin 74 3.3 Discussion 78 3.3.1 The streptozotocin-induced diabetes animal model .78 3.3.2 Nitric Oxide (NO): A limitation in the study of H2S derangement in streptozotocin-injected rats? 79 IV 3.3.3 H2S formation is altered in the liver and pancreas of streptozotocin injected rats. .81 The significance of deranged H2S formation in liver and pancreas of 3.3.4 streptozotocin-injected animals .83 Effect of H2S on insulin secretion from pancreatic β-cells 85 4.1 Introduction 85 4.2 Results 87 4.2.1 Effect of NaHS on cell viability, intracellular ATP, GSH and insulin 87 4.2.2 Effect of NaHS on HIT-T15 cell insulin secretion 90 4.2.3 Changes in cellular K+, Ca2+ and cell membrane polarity in the presence of NaHS 92 4.2.4 CBS Overexpression and Its Effect on Insulin Secretion in HIT-T15 cells 96 4.3 Discussion 100 4.3.1 NaHS reduces insulin secretion from pancreatic β-cells in culture .100 4.3.2 Proposed mechanism of NaHS-induced inhibition of insulin secretion 103 4.3.3 The significance of the H2S-mediated reduction in insulin secretion from pancreatic β-cells .106 Effect of H2S on rat aorta vascular contractility 108 5.1 Introduction 108 5.2 Results 110 5.2.1 NaHS-mediated contraction in rat aorta is dependent on endothelial cell presence .110 5.2.2 NaHS attenuates acetylcholine-mediated relaxation .114 V 5.2.3 NaHS attenuates SNP-mediated relaxation .122 5.2.4 NaHS attenuates histamine-mediated relaxation but not isoprenalinemediated relaxation 125 5.2.5 5.3 L-Cysteine attenuates acetylcholine-mediated relaxation .130 Discussion 133 5.3.1 NaHS-mediated contraction is dependent on the presence of the endothelium 133 5.3.2 NaHS interacts with NO and vascular endothelial cell-mediated relaxation of rat aortic rings .134 5.3.3 NaHS-mediated contraction of aortic rings is dependent on NO 137 5.3.4 Vascular-derived H2S may regulate NO function 139 5.3.5 A possible physiological role of H2S in vascular tissue 139 The role of H2S in the regulation of diabetic vasculature 142 6.1 Introduction 142 6.2 Results 144 6.2.1 Increased H2S formation in aorta of streptozotocin-diabetic rat 144 6.2.2 Altered Ach-mediated vasorelaxation in aortic rings from streptozotocin-injected rats 145 6.2.3 SNP-mediated relaxation in aorta of streptozotocin-injected rats .146 6.2.4 Altered NaHS-mediated vasoactivity in diabetic rat aortic rings 149 6.2.5 Altered L-cysteine-mediated vasoactivity in diabetic rat aortic rings151 6.2.6 Mean arterial blood pressure (MAP) changes in the streptozotocindiabetic rat 153 6.3 Discussion 155 VI The effect of PAG on plasma glucose and MAP in streptozotocin-diabetic rats 163 7.1 Introduction 163 7.2 Results 165 7.2.1 Effect of PAG treatment on diabetic rat weight and plasma insulin 165 7.2.2 Effect of PAG treatment on plasma glucose in diabetic rats .166 7.2.3 Effect of PAG treatment on plasma nitrite/ nitrate (NOx), plasma amylase and plasma glucagon in diabetic rats .169 7.2.4 Effect of PAG treatment on rat MAP and acetylcholine-mediated vasodepressor response in diabetic rats .173 Effect of PAG on rat plasma H2S and liver/pancreas H2S synthesis in 7.2.5 diabetic rats 175 7.3 Discussion 178 7.3.1 Effect of PAG treatment on H2S levels/production in rats 178 7.3.2 Effect of PAG on plasma insulin and glucagon in healthy and diabetic rats 179 7.3.3 Effect of PAG treatment on MAP in diabetic rats .182 General discussion and future work .184 8.1 H2S in regulation of insulin secretion 184 8.2 H2S in regulation of diabetic vasculature .188 8.3 Conclusion .193 References 194 VII Summary Diabetes mellitus is a serious complex disease characterized by hyperglycaemia which in turn induces vascular complications such as hypertension, retinopathy, nephropathy and artherosclerosis. Diabetes-related vascular complications form the bulk of patient morbidity and no single therapy to date has proved useful in abrogating diabetes-induced vascular aberrations. Hydrogen sulphide (H2S), a well-known noxious gas is naturally produced in mammals from L-cysteine. Derangement in H2S levels has been reported in a variety of diseases including hypertension, sepsis and haemorrhagic shock. However, there are no prior reports linking H2S to diabetes mellitus. The present study examines the role of H2S in streptozotocin-injected rats; a well-established model of type-I diabetes mellitus. Plasma H2S concentrations as well as H2S synthesis in various organs were compared in healthy and diabetic rats to determine whether diabetes involves the alteration of endogenously produced H2S. The biosynthesis of H2S in liver and pancreas was elevated in diabetic rats with concurrent increase in expression of H2S producing enzymes in these organs. Insulinoma (HIT-T15) cells in culture were exposed to NaHS (H2S donor) to determine whether H2S had a direct effect on insulin release from pancreatic β-cells. Insulin secretion was lower in HIT-T15 cells exposed to NaHS. With the use of glibenclamide (K-ATP channel inhibitor) and fluorogenic intracellular K+, Ca2+ and membrane polarity probes, the mechanism of H2S-mediated attenuation of insulin release was found to involve K-ATP channel function. Overexpressing CBS (H2S-producing enzyme) protein in HIT-15 cells likewise attenuated insulin release from HIT-T15 cells suggesting that endogenously produced H2S may also reduce insulin secretion pancreatic β-cells. To examine the role of H2S in diabetic vascular contractility, the aorta from the diabetic rat was isolated for in VIII vitro studies. H2S synthesis was elevated in diabetic rat aorta homogenates and diabetic aortic rings were more sensitive to H2S-mediated vascular responses compared with healthy aortic rings. The bolus (i.v.) administration of PAG, a CSE (H2S producing enzyme) inhibitor, to anaesthetized diabetic rats caused a modest but significant rise in mean arterial blood pressure (MAP) suggesting that H2S may contribute to diabetic vasculature and blood pressure aberrations. Diabetic rats were subsequently treated daily with PAG (i.p.) for days to examine the effect of reduced endogenous H2S levels in diabetes. PAG treatment did not alter either diabetic rat MAP or acetylcholine-mediated vasodepressor effects probably because PAG was not potent enough to inhibit H2S formation in the resistance arteries which contribute largely to rat blood pressure regulation. PAG treatment also reduced plasma insulin levels in healthy rats suggesting that PAG-related effects on other organs (perhaps the brain) may contribute to abnormal insulin regulation in the intact animal. 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Review. 218 [...]... the Singapore Ministry of Health estimated that the prevalence of diabetes mellitus was 6 per 1000 indicating that 12,000 new diabetes cases arise from the country each year Taken together, these data clearly shows that diabetes presents one of the major threats to global health in the 21st century 1.3 Release of insulin by pancreatic β-cells Insulin is the principal hormone that regulates uptake of. .. Vasorelaxant Effects of Hydrogen Sulfide and its Biosynthesis in the Human Internal Mammary Artery J Pharmacol Exp Ther Submitted XIV Conference Proceedings Ali MY, Tan KH, Moore PK (2005) Streptozotocin-induced diabetes mellitus in the rat is associated with enhanced biosynthesis of hydrogen sulphide Inflammation Research Supp 2: S192 Yusuf M, Low, CM, Whiteman M, Moore PK (2006) Hydrogen sulphide abrogates... cells Insulin binds and phosphorlyates the intracellular domain of the tyrosine kinase receptor Phosphorylation drives the recruitment of proteins (Shc, Grb2 and, Sos) that activate the Ras/ MAP Kinase pathway ERK subsequently activates and induces the translocation of transcriptional regulators c-Myc and Elk-1 into the nucleus This results in the transcription of various survival and growth genes in... cause of blindness, renal failure, nerve damage and gangrene-related amputations On the other hand, macrovascular complications of diabetes encompass atherosclerosis, coronary artery disease and peripheral artery disease As much as 80% of all diabetic deaths in North America occur as a result of atherosclerosis (American Diabetes Assoc., 1993) Furthermore, diabetes was shown to increase the risk of patient... patient susceptibility to cardiovascular disease and coronary heart disease by 200-500% (Feener & King, 1997) Although micro and macrovascular complications are defined by the specificity of the tissue involved, the induction and mechanisms of aberrations in both vascular complications are similar The pathogenesis of atherosclerosis was suggested to start with the loss in vascular endothelium function, which... overview of diabetes mellitus Diabetes mellitus is a complex disease characterized primarily by deranged metabolism and inappropriately high blood glucose concentrations (hyperglycemia) The aetiology of diabetes mellitus involves either low levels of the hormone insulin or abnormal resistance to insulin effects coupled with inadequate levels of insulin to compensate the resistance The hallmark symptoms of. .. synthesizing and releasing biologically active substances that modulate vascular tone (Figure 1.5) and influence vascular smooth muscle growth (Vane et al., 1990) The endothelium releases vascular constricting factors (EDCF) like endothelin-1 and angiotensin II which induce contraction in the underlying smooth muscle cells thereby narrowing the lumen of the blood vessel (Dhein et al., 1989) Endothelin... calcium channels and driving vasorelaxation Although the release of vasodilators reflects only a single aspect of the homeostatic role of the endothelium, endothelium dependent vasodilatation and in particular NO release is used as an accessible parameter to probe for endothelium function in diabetes (DeVriese et al., 2000) 11 Introduction Agonist R R Endothelial Cell EDRF EDHF EDCF PGI2 NO ET-1 Angiotensin... contribute significantly to vascular damage These reports also suggest that the loss of endothelium function (endothelial dysfunction) in diabetic animals takes precedence and may be a critical and initiating factor in the development of diabetes-related vascular disease 1.8 Mechanisms of endothelial dysfunction in diabetes Hyperglycaemia- and diabetes-related endothelial cell dysfunction have been suggested... Furthermore Palmer and colleagues (1998) reported that dietery supplementation of vitamin C and E in streptozotocin-diabetic rats for 4 weeks had no effect on the impaired Ach-mediated vasodilatation in the mesenteric arteries Therefore, the mixed results of ROS inhibition attenuating endothelial dysfunction in diabetes again suggests that increased vascular oxidation stress may only be one of the . advice with respect to the format of my thesis. I Table of Contents Acknowledgements I Table of Contents II Summary VIII List of Figures X List of Tables XIII List of publications XIV 1. making this thesis a reality. Many thanks go to the Thesis Advisory Committee (Associate Professor Madhav Bhatia, Associate Professor Benny Tan and Associate Professor Ed Manser) for their time. complications 9 1.6 Role of the vascular endothelium in maintaining blood pressure 10 1.7 Loss of vascular endothelium function in diabetes 13 1.8 Mechanisms of endothelial dysfunction in diabetes