PI3K Phosphorylation Is Linked to Improved Electrical Excitability in an In Vitro Engineered Heart Tissue Disease Model System

Tissue Eng Part A. 2015 Sep;21(17-18):2379-89. doi: 10.1089/ten.TEA.2014.0412. Epub 2015 Aug 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Chlorpropamide / analogs & derivatives
  • Chlorpropamide / pharmacology
  • Chromones / pharmacology
  • Disease Models, Animal
  • Electrophysiological Phenomena* / drug effects
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Heart / drug effects
  • Heart / physiology*
  • Insulin / pharmacology
  • Models, Biological
  • Morpholines / pharmacology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley
  • Tissue Engineering / methods*


  • API 2
  • Chromones
  • Insulin
  • Morpholines
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Chlorpropamide