title: Histidine button engineered into cardiac troponin I protects the ischemic and failing heart.
abstract: The myofilament protein troponin I (TnI) has a key isoform-dependent role in the development of contractile failure during acidosis and ischemia. Here we show that cardiac performance in vitro and in vivo is enhanced when a single histidine residue present in the fetal cardiac TnI isoform is substituted into the adult cardiac TnI isoform at codon 164. The most marked effects are observed under the acute challenges of acidosis, hypoxia, ischemia and ischemia-reperfusion, in chronic heart failure in transgenic mice and in myocytes from failing human hearts. In the isolated heart, histidine-modified TnI improves systolic and diastolic function and mitigates reperfusion-associated ventricular arrhythmias. Cardiac performance is markedly enhanced in transgenic hearts during reperfusion despite a high-energy phosphate content similar to that in nontransgenic hearts, providing evidence for greater energetic economy. This pH-sensitive 'histidine button' engineered in TnI produces a titratable molecular switch that 'senses' changes in the intracellular milieu of the cardiac myocyte and responds by preferentially augmenting acute and long-term function under pathophysiological conditions. Myofilament-based inotropy may represent a therapeutic avenue to improve myocardial performance in the ischemic and failing heart.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Sharlene M
authors.initials: SM
authors.lastname: Day
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Westfall
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Fomicheva
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoyer
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yasuda
authors.forename: Nathan C
authors.initials: NC
authors.lastname: La Cross
authors.forename: Louis G
authors.initials: LG
authors.lastname: D'Alecy
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Ingwall
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006333:Heart Failure / Q000378:metabolism* / Q000628:therapy; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000628:therapy; D032383:Myocytes, Cardiac / Q000378:metabolism; D015202:Protein Engineering; D051381:Rats; D019210:Troponin I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D019210:Troponin I; D006639:Histidine; D002118:Calcium