Lysophosphatidic acid-mediated augmentation of cardiomyocyte lipoprotein lipase involves actin cytoskeleton reorganization.
The lipoprotein lipase (LPL)-augmenting property of lysophosphatidylcholine requires the formation of lysophosphatidic acid (LPA) (J Mol Cell Cardiol 37: 931-938, 2004). Given that the actin cytoskeleton has been implicated in regulating cardiomyocyte LPL, we examined whether LPL secretion after LPA involves actin cytoskeleton reassembly. Incubation of myocytes with LPA (1-100 nM) increased basal and heparin-releasable LPL (HR-LPL), an effect that was independent of shifts in LPL mRNA. The influence of LPA on myocyte LPL was reflected at the coronary lumen, with substantial increases of the enzyme at this location. Incubation of myocytes with cytochalasin D not only blocked LPA-induced augmentation of HR-LPL but also abrogated filamentous actin formation. These effects of LPA were likely receptor mediated. Exposure of myocytes to LPA facilitated significant membrane translocation of RhoA and its downstream effector Rho kinase I (ROCK I), and blocking this effect with Y-27632 appreciably reduced basal and HR-LPL activity. Incubation of adipose tissue with LPA also significantly enhanced basal and HR-LPL activity, suggesting that sarcomeric actin likely has a limited role in influencing the LPL secretory function of LPA in the myocyte. Comparable to LPA, hyperglycemia also caused significant membrane translocation of RhoA and ROCK I in hearts isolated from diazoxide-treated animals, effects that were abrogated using insulin. Overall, our data suggest that comparable to hyperglycemia, LPA-induced increases in cardiac LPL occurred via posttranscriptional mechanisms and processes that likely required RhoA activation and actin polymerization. Whether this increase in LPL augments triglyceride deposition in the heart leading to eventual impairment in contractile function is currently unknown.
Pulinilkunnil
Thomas
T
Div. of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The Univ. of British Columbia, 2146 East Mall, Vancouver, British Columbia, Canada. rodrigue@interchange.ubc.ca
An
Ding
D
Ghosh
Sanjoy
S
Qi
Dake
D
Kewalramani
Girish
G
Yuen
Gloria
G
Virk
Naureen
N
Abrahani
Ashraf
A
Rodrigues
Brian
B
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure*; D017931:DNA Primers; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000199:Actins; D017931:DNA Primers; D008246:Lysophospholipids; D012333:RNA, Messenger; D008071:Lipoprotein Lipase; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid