title: PI3K Phosphorylation Is Linked to Improved Electrical Excitability in an In Vitro Engineered Heart Tissue Disease Model System.
abstract: Myocardial infarction, a prevalent cardiovascular disease, is associated with cardiomyocyte cell death, and eventually heart failure. Cardiac tissue engineering has provided hopes for alternative treatment options, and high-fidelity tissue models for drug discovery. The signal transduction mechanisms relayed in response to mechanoelectrical (physical) stimulation or biochemical stimulation (hormones, cytokines, or drugs) in engineered heart tissues (EHTs) are poorly understood. In this study, an EHT model was used to elucidate the signaling mechanisms involved when insulin was applied in the presence of electrical stimulation, a stimulus that mimics functional heart tissue environment in vitro. EHTs were insulin treated, electrically stimulated, or applied in combination (insulin and electrical stimulation). Electrical excitability parameters (excitation threshold and maximum capture rate) were measured. Protein kinase B (AKT) and phosphatidylinositol-3-kinase (PI3K) phosphorylation revealed that insulin and electrical stimulation relayed electrical excitability through two separate signaling cascades, while there was a negative crosstalk between sustained activation of AKT and PI3K.
authors.affiliation: 1 Institute of Biomaterials and Biomedical Engineering , Toronto, Canada .
authors.forename: Kujaany
authors.initials: K
authors.lastname: Kana
authors.affiliation: 1 Institute of Biomaterials and Biomedical Engineering , Toronto, Canada .
authors.forename: Hannah
authors.initials: H
authors.lastname: Song
authors.affiliation: 2 Department of Chemical Engineering and Applied Chemistry, University of Toronto , Canada .
authors.forename: Carol
authors.initials: C
authors.lastname: Laschinger
authors.affiliation: 1 Institute of Biomaterials and Biomedical Engineering , Toronto, Canada .|3 Heart & Stroke/Richard Lewar Centre of Excellence , Toronto, Canada .|4 McEwen Centre for Regenerative Medicine, University of Health Network , Toronto, Canada .
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
authors.affiliation: 1 Institute of Biomaterials and Biomedical Engineering , Toronto, Canada .|2 Department of Chemical Engineering and Applied Chemistry, University of Toronto , Canada .|3 Heart & Stroke/Richard Lewar Centre of Excellence , Toronto, Canada .
authors.forename: Milica
authors.initials: M
authors.lastname: Radisic
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D023822:Tissue Engineering / Q000379:methods*; D000096926:Benzenesulfonamides
chemical_list: D002747:Chlorpropamide; D002867:Chromones; D007328:Insulin; D009025:Morpholines; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; C111224:API 2; D000096926:Benzenesulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one