title: Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes.
abstract: Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis.
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.|Heart Failure Pharmacology, Baker IDI Heart &Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Hooi Hooi
authors.initials: HH
authors.lastname: Ng
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Chen Huei
authors.initials: CH
authors.lastname: Leo
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.|Heart Failure Pharmacology, Baker IDI Heart &Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Darnel
authors.initials: D
authors.lastname: Prakoso
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart &Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Chengxue
authors.initials: C
authors.lastname: Qin
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart &Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Parry
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage; D012065:Relaxin / Q000008:administration & dosage*; D013311:Streptozocin
chemical_list: D011994:Recombinant Proteins; C577649:serelaxin protein, human; D013311:Streptozocin; D012065:Relaxin