HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0832v1 57/1/64    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, M. S. Articles by Rodrigues, B. Search for Related Content PubMed PubMed Citation Articles by Kim, M. S. Articles by Rodrigues, B. Social Bookmarking                What's this?

Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase–Dependent Actin Cytoskeleton Organization

Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada

Address correspondence and reprint requests to Dr. B. Rodrigues, Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. E-mail: rodrigue{at}interchange.ubc.ca

Key Words: AICAR, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside • AMPK, AMP-activated protein kinase • CTD, cytochalasin D • Hsp, heat shock protein • HSPG, heparan sulfate proteoglycan • LPL, lipoprotein lipase • MAPK, mitogen-activated protein kinase • NEFA, nonesterified fatty acid • siRNA, small interfering RNA

OBJECTIVE—Heart disease is a leading cause of death in diabetes and could occur because of excessive use of fatty acid for energy generation. Our objective was to determine the mechanisms by which AMP-activated protein kinase (AMPK) augments cardiac lipoprotein lipase (LPL), the enzyme that provides the heart with the majority of its fatty acid.

RESEARCH DESIGN AND METHODS—We used diazoxide in rats to induce hyperglycemia or used 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) and thrombin to directly stimulate AMPK and p38 mitogen-activated protein kinase (MAPK), respectively, in cardiomyocytes.

RESULTS—There was a substantial increase in LPL at the coronary lumen following 4 h of diazoxide. In these diabetic animals, phosphorylation of AMPK, p38 MAPK, and heat shock protein (Hsp)25 produced actin cytoskeleton rearrangement to facilitate LPL translocation to the myocyte surface and, eventually, the vascular lumen. AICAR activated AMPK, p38 MAPK, and Hsp25 in a pattern similar to that seen with diabetes. AICAR also appreciably enhanced LPL, an effect reduced by preincubation with the p38 MAPK inhibitor SB202190 or by cytochalasin D, which inhibits actin polymerization. Thrombin activated p38 MAPK in the absence of AMPK phosphorylation. Comparable with diabetes, activation of p38 MAPK and, subsequently, Hsp25 phosphorylation and F-actin polymerization corresponded with an enhanced LPL activity. SB202190 and silencing of p38 MAPK also prevented these effects induced by thrombin and AICAR, respectively.

CONCLUSIONS—We propose that AMPK recruitment of LPL to the cardiomyocyte surface (which embraces p38 MAPK activation and actin cytoskeleton polymerization) represents an immediate compensatory response by the heart to guarantee fatty acid supply when glucose utilization is compromised.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?