Pak1 is required to maintain ventricular Ca²⁺ homeostasis and electrophysiological stability through SERCA2a regulation in mice.

Abstract

BACKGROUND:

Impaired sarcoplasmic reticular Ca(2+) uptake resulting from decreased sarcoplasmic reticulum Ca(2+)-ATPase type 2a (SERCA2a) expression or activity is a characteristic of heart failure with its associated ventricular arrhythmias. Recent attempts at gene therapy of these conditions explored strategies enhancing SERCA2a expression and the activity as novel approaches to heart failure management. We here explore the role of Pak1 in maintaining ventricular Ca(2+) homeostasis and electrophysiological stability under both normal physiological and acute and chronic β-adrenergic stress conditions.

METHODS AND RESULTS:

Mice with a cardiomyocyte-specific Pak1 deletion (Pak1(cko)), but not controls (Pak1(f/f)), showed high incidences of ventricular arrhythmias and electrophysiological instability during either acute β-adrenergic or chronic β-adrenergic stress leading to hypertrophy, induced by isoproterenol. Isolated Pak1(cko) ventricular myocytes correspondingly showed aberrant cellular Ca(2+) homeostasis. Pak1(cko) hearts showed an associated impairment of SERCA2a function and downregulation of SERCA2a mRNA and protein expression. Further explorations of the mechanisms underlying the altered transcriptional regulation demonstrated that exposure to control Ad-shC2 virus infection increased SERCA2a protein and mRNA levels after phenylephrine stress in cultured neonatal rat cardiomyocytes. This was abolished by the Pak1-knockdown in Ad-shPak1-infected neonatal rat cardiomyocytes and increased by constitutive overexpression of active Pak1 (Ad-CAPak1). We then implicated activation of serum response factor, a transcriptional factor well known for its vital role in the regulation of cardiogenesis genes in the Pak1-dependent regulation of SERCA2a.

CONCLUSIONS:

These findings indicate that Pak1 is required to maintain ventricular Ca(2+) homeostasis and electrophysiological stability and implicate Pak1 as a novel regulator of cardiac SERCA2a through a transcriptional mechanism.

• Authors: Yanwen Wang, Hoyee Tsui, Yunbo Ke, Ying Shi, Yatong Li, Laura Davies, Elizabeth J Cartwright, Luigi Venetucci, Henggui Zhang, Derek A Terrar, Christopher L-H Huang, R John Solaro, Xin Wang, Ming Lei
• Journal: Circulation. Arrhythmia and electrophysiology (Circ Arrhythm Electrophysiol) Vol. 7 Issue 5 Pg. 938-48 (Oct 2014) ISSN: 1941-3084 [Electronic] United States
• PMID: 25217043 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Adrenergic beta-Agonists
• Atp2a2 protein, rat
• RNA, Messenger
• Pak1 protein, mouse
• Pak1 protein, rat
• p21-Activated Kinases
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Atp2a2 protein, mouse
• Isoproterenol
• Calcium

Topics

• Adrenergic beta-Agonists
• Animals
• Calcium (metabolism)
• Cardiac Pacing, Artificial
• Cardiomegaly (enzymology)
• Cells, Cultured
• Disease Models, Animal
• Electrocardiography
• Gene Expression Regulation, Enzymologic
• Heart Ventricles (enzymology, physiopathology)
• Homeostasis
• Isoproterenol
• Male
• Mice, Knockout
• Myocytes, Cardiac (enzymology)
• RNA Interference
• RNA, Messenger (metabolism)
• Rats
• Risk Factors
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (genetics, metabolism)
• Tachycardia, Ventricular (chemically induced, enzymology, genetics, physiopathology)
• Time Factors
• Transcription, Genetic
• Transfection
• p21-Activated Kinases (deficiency, genetics, metabolism)