Faculty Collaboration Database

Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo. Am J Physiol Heart Circ Physiol 2004 Jun;286(6):H2089-95

Date

01/17/2004

Pubmed ID

14726296

DOI

10.1152/ajpheart.00582.2003

Scopus ID

2-s2.0-2542498796 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

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-epsilon, may slow the rates of cardiac contraction and relaxation (+dP/dt and -dP/dt). To explore this issue in vivo, we employed transgenic mice [mutant TnI (mTnI) mice] in which the major PKC phosphorylation sites on cardiac TnI were mutated by alanine substitutions for Ser(43) and Ser(45) and studied in situ hemodynamics at baseline and increased inotropy. Hearts from mTnI mice exhibited increased contractility, as shown by a 30% greater +dP/dt and 18% greater -dP/dt than FVB hearts, and had a negligible response to isoproterenol compared with 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.

Author List

Roman BB, Goldspink PH, Spaite E, Urboniene D, McKinney R, Geenen DL, Solaro RJ, Buttrick PM

MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Cardiomegaly
Cardiotonic Agents
Coronary Circulation
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Echocardiography
Isoproterenol
Male
Mice
Mice, Transgenic
Mutagenesis
Myocardial Contraction
Phosphorylation
Protein Kinase C
Protein Kinase C-epsilon
Troponin I