title: Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury.
abstract: Mice expressing the tetracycline transactivator (tTA) transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA) are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between α-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions. Protection against ischemia/reperfusion injury was assessed using isolated perfused hearts where α-MHC-tTA mice had robust protection against ischemia/reperfusion injury which was not blocked by pharmacological inhibition of PI3Ks with LY294002. Furthermore, α-MHC-tTA mice subjected to coronary artery ligation exhibited significantly reduced infarct size compared to control animals. Our findings reveal that α-MHC-tTA transgenic mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury similar to cardiac pre- and post-conditioning effects. However, in contrast to classical pre- and post-conditioning, the α-MHC-tTA phenotype is not inhibited by the classic preconditioning inhibitor LY294002 suggesting involvement of a non-PI3K-AKT signaling pathway in this phenotype. Thus, further study of the α-MHC-tTA model may reveal novel molecular targets for therapeutic intervention during ischemic injury.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois-Chicago, Chicago, Illinois, United States of America.
authors.forename: Laila
authors.initials: L
authors.lastname: Elsherif
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
authors.forename: Milana
authors.initials: M
authors.lastname: Grachoff
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
authors.forename: David L
authors.initials: DL
authors.lastname: Geenen
authors.forename: John P
authors.initials: JP
authors.lastname: O'Bryan
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D004452:Echocardiography; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D009929:Organ Size; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000503:physiopathology*; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics*; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015534:Trans-Activators; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003402:Creatine Kinase; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D013752:Tetracycline