Abstract 19829: PKIalpha Modulates Adrenergic Signaling in Cardiac Physiology and Pathophysiology
Introduction: Protein kinase inhibitor peptide α (PKIα) isoforms are abundantly expressed endogenous inhibitors of PKA in the heart. The physiological and pathophysiological relevance of PKIα has not been studied.
Hypothesis: PKIα is an endogenous regulator of β-adrenergic response in normal and post-myocardial infarction (MI) hearts.
Methods: PKIα knockout (KO) and c57bl/6 control (CTR) mice were used to test if PKIα affected cardiac β-adrenergic response and if played a role in post-MI hearts.
Results: Protein abundance of PKIα, but not the other PKI isoforms (PKIβ and PKIγ), was significantly increased in failing human and post-MI mouse ventricles compared to in control ventricles. The loss of PKIα in mice did not affect the expression of the other two PKI isoforms. Nor did it change the expression of PKA regulatory and catalytic subunits. In vivo cardiac function was evaluated by conventional echocardiography (ECHO) in PKIα KO mice did not show alterations in basal cardiac morphology, function and life span of mice. However, when in vivo and ex vivo cardiac β-adrenergic response was determined by intra-LV hemodynamic measurements in response to different doses of isoproterenol, the loss of PKIα sensitizes the heart in response to ISO and the maximum dp/dt increases more (by 25%) in KO mice than in control mice. Isolated ventricular myocytes were used to determine cellular responses to β-adrenergic agonist, isoproterenol (ISO, 10nM and 100nM). PKI KO myocytes were more sensitive to ISO in that 10nM ISO increased myocyte contraction and Ca2+ transient amplitudes more in KO myocytes. At the ISO concentration of 10-9M, ISO increased more phosphorylation of the Ser16 site (PKA site) on phospholamban. In post-MI animals, the loss of PKIα enhances cardiac function in the short term but in a longer term it caused more myocardial infarction and depression in cardiac function.
Conclusions: PKIα may blunt cardiac β-adrenergic responses by antagonizing PKA. This mechanism could be protective to avoid β-adrenergic overstimulation, especially in post-MI patients and animal models.
Author Disclosures: X. Zhang: None. Y. Li: None. X. Ai: None. M. Tang: None. X. Hua: None. X. Chen: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.