title: HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO.
abstract: Nitroxyl (HNO) is a redox congener of NO. We now directly compare the antihypertrophic efficacy of HNO and NO donors in neonatal rat cardiomyocytes and compare their contributing mechanisms of actions in this setting. Isopropylamine-NONOate (IPA-NO) elicited concentration-dependent inhibition of endothelin-1 (ET1)-induced increases in cardiomyocyte size, with similar suppression of hypertrophic genes. Antihypertrophic IPA-NO actions were significantly attenuated by l-cysteine (HNO scavenger), Rp-8-pCTP-cGMPS (cGMP-dependent protein kinase inhibitor), and 1-H-(1,2,4)-oxodiazolo-quinxaline-1-one [ODQ; to target soluble guanylyl cyclase (sGC)] but were unaffected by carboxy-PTIO (NO scavenger) or CGRP8-37 (calcitonin gene-related peptide antagonist). Furthermore, IPA-NO significantly increased cardiomyocyte cGMP 3.5-fold (an l-cysteine-sensitive effect) and stimulated sGC activity threefold, without detectable NO release. IPA-NO also suppressed ET1-induced cardiomyocyte superoxide generation. The pure NO donor diethylamine-NONOate (DEA-NO) reproduced these IPA-NO actions but was sensitive to carboxy-PTIO rather than l-cysteine. Although IPA-NO stimulation of purified sGC was preserved under pyrogallol oxidant stress (in direct contrast to DEA-NO), cardiomyocyte sGC activity after either donor was attenuated by this stress. Excitingly IPA-NO also exhibited acute antihypertrophic actions in response to pressure overload in the intact heart. Together these data strongly suggest that IPA-NO protection against cardiomyocyte hypertrophy is independent of both NO and CGRP but rather utilizes novel HNO activation of cGMP signaling. Thus HNO acutely limits hypertrophy independently of NO, even under conditions of elevated superoxide. Development of longer-acting HNO donors may thus represent an attractive new strategy for the treatment of cardiac hypertrophy, as stand-alone and/or add-on therapy to standard care.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Irvine
authors.forename: Nga
authors.initials: N
authors.lastname: Cao
authors.forename: Swati
authors.initials: S
authors.lastname: Gossain
authors.forename: Amy E
authors.initials: AE
authors.lastname: Alexander
authors.forename: Jane E
authors.initials: JE
authors.lastname: Love
authors.forename: Chengxue
authors.initials: C
authors.lastname: Qin
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D006332:Cardiomegaly / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism*; D011748:Pyrogallol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects*; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors
chemical_list: C507406:1-isopropyldiazen-1-ium-1,2-diolate; D000975:Antioxidants; D002317:Cardiovascular Agents; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006834:Hydrazines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D018160:Receptors, Cytoplasmic and Nuclear; D011748:Pyrogallol; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C039900:nitroxyl; D006152:Cyclic GMP
keywords: cGMP-dependent protein kinase; cardiac hypertrophy; nitric oxide; nitroxyl; superoxide