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1 Center for Cardiovascular Sciences, University of Illinois at Chicago, Chicago, Illinois, USA; Center for Cardiovascular Sciences, Depts of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
2 Center for Cardiovascular Sciences, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
3 Center for Cardiovascular Sciences, University of Illinois at Chicago, Chicago, Illinois, USA; Center for Cardiovascular Sciences, Depts of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, USA
* To whom correspondence should be addressed. E-mail: broman{at}uic.edu.
Protein kinase C (PKC) modulates cardiomyocyte function by phosphorylation of intracellular targets including myofilament proteins. Data generated from studies on in vitro heart preparations indicate that PKC phosphorylation of troponin I (TnI), primarily via PKC-
, may slow the rates of cardiac contraction and relaxation. To explore this issue in vivo, we employed transgenic mice (mTnI) in which the major PKC phosphorylation sites on cardiac TnI were mutated by alanine substitutions for serine 43 and 45, and studied in situ hemodynamics at baseline and increased inotropy. Hearts from mTnI mice exhibited increased contractility as shown by 30% greater +dP/dt and 18% greater -dP/dt than FVB hearts, and had a negligible
response to isoproterenol compared to FVB mice in which +dP/dt increased by 33% and -dP/dt increased by 26%. Treatment with phenylephrine and propranolol gave a similar result; FVB mouse hearts demonstrated a 20% increase in developed pressure, whereas mTnI mice showed no response. Back phosphorylation of TnI from mTnI hearts demonstrated that the mutation of the PKC sites was associated with an enhanced PKA dependent phosphorylation independent of a change in basal cAMP levels. Our results demonstrate the important role that PKC dependent phosphorylation of TnI has on the modulation of cardiac function under basal as well as augmented states and indicate interdependence of the phosphorylation sites of TnI in hearts beating in situ.
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