title: Antisense versus proopiomelanocortin mRNA reduces vascular risk in a murine model of type-2 diabetes following stress exposure in early post-natal life.
abstract: Mechanisms of vascular complications in type-2 diabetes patients and animal models are matter of debate. We previously demonstrated that a double-stress model applied to male mice during nursing period produces enduring hyperfunction of endogenous opioid and adrenocorticotropin (ACTH)-corticosteroid systems, accompanied by type-2 diabetes-like alterations in adult animals. Administration of the opioid receptor antagonist naloxone, or of an antisense oligodeoxynucleotide versus proopiomelanocortin mRNA, capable to block the pro-opiomelanocortin-derived peptides β-endorphin and ACTH, selectively prevent these alterations. Here, we investigated alterations produced by our stress model on aorta endothelium-dependent relaxation and contractile responses. Mice, stressed during nursing period, showed in the adulthood hormonal and metabolic type-2 diabetes-like alterations, including hyperglycemia, increased body weight and increased plasma ACTH and corticosterone levels. Ex vivo isolated aorta rings, gathered from stressed mice, were less sensitive to noradrenaline-induced contractions versus controls. This effect was blocked by nitric-oxide synthase-inhibitor l-N(G)-nitroarginine added to bath organ solution. Aorta rings relaxation caused by acetylcholine was enhanced in stressed mice versus controls, but following treatment with the nitric-oxide donor sodium nitroprusside, concentration-relaxation curves in aorta from stressed groups were similar to controls. Therefore, vascular response alterations to physiologic-pharmacologic stimuli were apparently due to nitric-oxide hyperfunction-dependent mechanisms. Aorta functional alterations, and plasma stress hormones enhancement, were prevented in mice stressed and treated with antisense oligodeoxinucleotide, addressed to reduce ACTH- and corticosteroid-mediated hyperfunction. This study demonstrates the key role of ACTH-corticosteroid axis hyperfunction for the triggering of vascular conditions in male adult rodents following postnatal stress in a type-2 diabetes model.
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, via Regina Elena 299, 00161 Roma, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Loizzo
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Santi M
authors.initials: SM
authors.lastname: Spampinato
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, via Regina Elena 299, 00161 Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fortuna
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, via Regina Elena 299, 00161 Roma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Vella
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, via Regina Elena 299, 00161 Roma, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Fabi
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, via Regina Elena 299, 00161 Roma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Del Basso
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Campana
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, via Regina Elena 299, 00161 Roma, Italy. Electronic address: stefano.loizzo@iss.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Loizzo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016375:Antisense Elements (Genetics) / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D011333:Pro-Opiomelanocortin / Q000037:antagonists & inhibitors* / Q000235:genetics; D013312:Stress, Physiological / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D016375:Antisense Elements (Genetics); D011333:Pro-Opiomelanocortin
keywords: Antisense oligodeoxinucleotide; Aorta; Diabetes vascular complications; Nitric oxide; Postnatal stress; β-Endorphin