Published online before print June 26, 2008, doi: 10.1161/CIRCRESAHA.108.178681
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© 2008 American Heart Association, Inc.
Molecular Medicine |
Protein Kinase D Is a Key Regulator of Cardiomyocyte Lipoprotein Lipase Secretion After Diabetes
From the Faculty of Pharmaceutical Sciences (M.S.K., F.W., P.P., G.K., E.H., N.N., U.K., A.A., B.R.), the Department of Pediatrics (S.I.), and the Department of Biochemistry and Molecular Biology (Y.W., C.G.P.), UBC, Vancouver, Canada.
Correspondence to Dr B. Rodrigues, Faculty of Pharmaceutical Sciences, UBC, 2146 East Mall, Vancouver, B.C., Canada V6T 1Z3. E-mail rodrigue{at}interchange.ubc.ca
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Abstract |
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The diabetic heart switches to exclusively using fatty acid (FA) for energy supply and does so by multiple mechanisms including hydrolysis of lipoproteins by lipoprotein lipase (LPL) positioned at the vascular lumen. We determined the mechanism that leads to an increase in LPL after diabetes. Diazoxide (DZ), an agent that decreases insulin secretion and causes hyperglycemia, induced a substantial increase in LPL activity at the vascular lumen. This increase in LPL paralleled a robust phosphorylation of Hsp25, decreasing its association with PKC
, allowing this protein kinase to phosphorylate and activate protein kinase D (PKD), an important kinase that regulates fission of vesicles from the golgi membrane. Rottlerin, a PKC inhibitor, prevented PKD phosphorylation and the subsequent increase in LPL. Incubating control myocytes with high glucose and palmitic acid (Glu+PA) also increased the phosphorylation of Hsp25, PKC, and PKD in a pattern similar to that seen with diabetes, in addition to augmenting LPL activity. In myocytes in which PKD was silenced or a mutant form of PKC was expressed, high Glu+PA were incapable of increasing LPL. Moreover, silencing of cardiomyocyte Hsp25 allowed phorbol 12-myristate 13-acetate to elicit a significant phosphorylation of PKC, an appreciable association between PKC and PKD, and a vigorous activation of PKD. As these cells also demonstrated an additional increase in LPL, our data imply that after diabetes, PKD control of LPL requires dissociation of Hsp25 from PKC, association between PKC and PKD, and vesicle fission. Results from this study could help in restricting cardiac LPL translocation, leading to strategies that overcome contractile dysfunction after diabetes.
Key Words: heat shock protein • protein kinase C • hyperglycemia • hyperlipidemia • vesicles
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Introduction |
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Cardiac muscle has a high demand for energy and uses multiple substrates, including fatty acid (FA), carbohydrate, amino acids, and ketones.1 Among these substrates, carbohydrate and FA are the major sources from which the heart derives most of its energy. In a normal heart, whereas glucose and lactate account for approximately 30% of energy provided to the cardiac muscle, 70% of ATP generation is through FA oxidation.2 FA delivery and utilization by the heart involves: (1) release from adipose tissue and transport to the heart after complexing with albumin,3 (2) provision through breakdown of endogenous cardiac triglyceride (TG) stores,4 (3) internalization of whole lipoproteins,5 and (4) hydrolysis of circulating TG-rich lipoproteins to FA by lipoprotein lipase (LPL) positioned at the endothelial surface of the coronary lumen.6 The molar concentration of FA bound to albumin is
10-fold less than that of FA in lipoprotein-TG,7 and LPL-mediated hydrolysis of circulating TG-rich lipoproteins to FA is suggested to be the principal source of FA for cardiac utilization.8 Coronary endothelial cells do not synthesize LPL.9 In the heart, this enzyme is produced in cardiomyocytes and subsequently secreted onto heparan sulfate proteoglycan (HSPG) binding sites on the myocyte cell surface.10 From here, LPL is transported onto comparable binding sites on the luminal surface of endothelial cells.11
The earliest change that occurs in the diabetic heart is altered energy metabolism where in the presence of lower glucose utilization, the heart switches to exclusively using FA for energy supply.12 It does this by increasing its LPL activity at the coronary lumen.8 We have examined LPL biology in the diabetic heart and have determined that the augmented activity13 is: (1) not the result of increased gene expression,13 (2) unrelated to an increase in the number of capillary endothelial HSPG binding sites,13 (3) acutely (hours) regulated by short-term changes in insulin,14 and (4) functionally relevant and capable of hydrolyzing lipoprotein-TG.15 More recently, we have examined the contributions of the endothelial cell and the cardiomyocyte in enabling this increased enzyme at the vascular lumen. At the endothelial cell, we reported that TG16 and lipoprotein breakdown products like lysophosphatidylcholine,17 likely through their release of heparanase, enabled myocyte HSPG cleavage and transfer of LPL toward the coronary lumen. Within the myocyte, recruitment of LPL to the cell surface was controlled by stress kinases like AMPK and p38 MAPK, which allowed for actin cytoskeleton polymerization and provision of a network that facilitated LPL movement.18 In the present study, we determined the mechanism that controls cardiac LPL vesicular trafficking after diabetes. Our data suggest that protein kinase D (PKD) activation is essential for LPL vesicle formation and its movement to the cardiomyocyte plasma membrane, for eventual translocation to the coronary vascular lumen.
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Materials and Methods |
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An expanded version of the materials and methods has been described in the online Data Supplement available at http://circres. ahajournals.org. In this supplement, we have explained our animal model of diabetes,19,20 perfusion of isolated hearts,18,21 isolation of cardiomyocytes,20,13 assay for LPL activity,14 adenoviral transfection of cardiac cells,22 Western Blotting,23 immunoprecipitation, immunofluorescence, gene silencing,18 and measurement of cardiac diacylglycerol.24
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Results |
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Characterization of the Model of Acute Diabetes Induced With Diazoxide
Subsequent to injection of DZ, blood glucose levels increased and were significantly higher after 1 and 4 hours (supplemental Table I). Changes in plasma parameters with DZ also included significant and rapid increases in FA (supplemental Table I). Retrograde perfusion of hearts with heparin resulted in release of LPL into the coronary perfusate. Compared to control rat hearts, there was a substantial increase in LPL activity at the vascular lumen after 1 and 4 hours of DZ (supplemental Table I). We have previously shown that this change in LPL activity was independent of shifts in mRNA,13 and was dependent on its lowering of insulin rather than its direct effects on the heart or blood pressure.20 Incubation of cardiomyocytes with DZ (1 mg/mL; calculated concentration in vivo) had no influence on heparin releasable (HR) LPL activity (supplemental Figure I).
Mechanism of Activation of PKD in Hearts From Animals With Hyperglycemia
Recently, we have determined that diabetes increases the phosphorylation of Hsp25.18 In the present study, we duplicated this result (Figure 1A) and additionally show that Hsp25 phosphorylation enables PKC to dissociate from Hsp25 (Figure 1B). As Hsp25 binds directly to ser-643 of PKC, its separation permits PKC phosphorylation (Figure 1C), with an associated increase in its activity.25 PKC has been suggested to regulate PKD activity in intestinal epithelial cells.26 Interestingly, in addition to PKC phosphorylation, DZ also augmented PKD phosphorylation at 1 and 4 hours after injection (Figure 1E). This increase in PKD phosphorylation paralleled a robust attachment of phospho-PKC to PKD (Figure 1D). Injection of STZ precipitated overt hyperglycemia (supplemental Table I). Compared to control hearts, LPL activity increased at the vascular lumen after 1 and 7 days of STZ (Figure 1F). As observed with DZ, this increase in LPL activity with STZ diabetes closely paralleled activation of PKD (Figure 1G).
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Role of PKD in Diabetes Induced Augmentation of LPL Activity
PKD assists in protein transport from the golgi to plasma membrane.27 We hypothesized that after DZ, activation of PKD facilitates LPL vesicular movement to the cardiomyocyte cell surface and eventually to the vascular lumen, and that its inhibition should reduce LPL activity at this location. In the absence of specific inhibitors of PKD, we used rottlerin, an inhibitor of PKC. Treatment of rottlerin for 1 hour decreased PKD phosphorylation that is produced after DZ (Figure 2A). More importantly, the remarkable increase in LPL immunofluroscence (Figure 2B) or activity (Figure 2C) at the vascular lumen after 4 hours of DZ was also reduced by preincubation with rottlerin.
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Simulation of Diabetes Promotes LPL Trafficking to the Cardiomyocyte Plasma Membrane
We duplicated the hyperglycemia and hyperlipidemia observed after DZ by incubating control myocytes with high glucose and palmitic acid (Glu+PA). 20 mmol/L glucose with 1.5 mmol/L PA increased the phosphorylation of Hsp25 (Figure 3A), PKC (Figure 3B), and PKD (Figure 3C) in a pattern similar to that seen with diabetes induced by DZ. Once activated, PKD regulates formation of transgolgi vesicles and facilitates their movement to the plasma membrane with help of vesicle associated membrane protein (VAMP).28 High Glu+PA brought about both PKD and VAMP translocation, as measured by Western blotting and confocal microscopy (Figure 4A and 4B). Interestingly, this milieu also augmented cardiomyocyte cell surface HR-LPL activity (Figure 4C) and protein (Figure 5B, middle panel). Independently, high glucose or PA (supplemental Figure IV), and mannitol with PA (Figure 4C) had no effect on cardiomyocyte LPL trafficking. Additionally, high glucose in the presence of physiologically relevant concentrations of PA (0.5 mmol/L) did not change HR-LPL activity, which only increased with 1 and 1.5 mmol/L PA (supplemental Figure II). Finally, unlike PA, oleic acid (1.5 mmol/L) in the presence of high glucose had no influence in increasing HR-LPL activity (supplemental Figure III).
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Silencing of PKD Prevents Cardiomyocyte LPL Recruitment Observed With High Glu+PA
To confirm the relationship between PKD and LPL, we used siRNA to silence PKD expression in isolated cardiomyocytes. We first validated successful PKD inhibition using Western blotting (Figure 5A, inset). In myocytes in which PKD was silenced, high Glu+PA had no influence on total PKD, which remained low in the PKD knockdown cells (Figure 5A). Interestingly, in myocytes in which PKD was silenced, high Glu+PA was incapable of increasing LPL immunofluorescence (Figure 5B) and activity (Figure 5C) at the cardiomyocyte cell surface.
Hsp25 Impedes the Action PMA to Phosphorylate PKC
As high Glu+PA induced a 1.4-fold increase in DAG (Con-2241±146, Glu+FA-3136±360 ng/106 cells; P<0.05), which is known to activate PKC, we incubated control myocytes with PMA, a DAG mimetic. Under our conditions, PMA was unable to phosphorylate PKC (Figure 6B). We hypothesized that as Hsp25 masks the catalytic site of PKC,29 silencing of Hsp25 would permit PMA to promote phosphorylation of PKC. We validated successful Hsp25 inhibition using Western blotting (Figure 6A, inset). In myocytes in which Hsp25 was silenced, PMA had no influence on total Hsp25, which remained low in the Hsp25 knockdown cells (Figure 6A). Surprisingly, in these cells, PKC phosphorylation increased (Figure 6B) with an associated amplification in its interaction with PKD (Figure 6C). As predicted, in myocytes in which Hsp25 was silenced, PMA was now able to induce significant phosphorylation of PKC (Figure 6B). More importantly, in the presence of PMA, Hsp25 knockdown cells demonstrated a strong interaction between PKC and PKD (Figure 6C).
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Significantly different from silenced Hsp25-Con, P<0.05. PMA, phorbol 12-myristate 13-acetate.
Directly Activating PKD Enlarges the Cardiomyocyte Cell Surface LPL Pool
Given the relationship between PKD and LPL movement, we determined PKD phosphorylation in Hsp25 silenced myocytes. Simply knocking down Hsp25 augmented PKD phosphorylation (Figure 7A), accelerated its translocation to the plasma membrane (Figure 7B), and enlarged LPL immunofluorescence (Figure 7B) and activity at the cardiomyocyte cell surface (Figure 7C). In these cells, PMA brought about an even greater phosphorylation and translocation of PKD (Figure 7A and 7B) with associated enlargement in LPL immunofluorescence (Figure 7B) and activity (Figure 7C).
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PKD Phosphorylation Requires Prior Activation of PKC
PKC expression increased after infection with adenoviral vectors encoding WT and DN PKC (Figure 8A). We have previously reported that overexpression of the DN PKC does not increase its activity.22 In PKC DN myocytes, high glucose and PA failed to increase phospho PKD (Figure 8A) and completely abrogated the increase in HR-LPL activity (Figure 8B).
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Discussion |
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During diabetes, when cardiac glucose uptake, glycolysis, and pyruvate oxidation are impaired, the heart rapidly adapts to using FA exclusively for ATP generation.30 This change occurs not only as a consequence of increased FA supply (attributable to an increased release of FA from adipose tissue and hydrolysis of TG-rich lipoproteins by LPL), but also through an intrinsic adaptation/maladaptation to elevated FA that includes an augmented FA oxidation and expression of genes that control utilization of this substrate.31 Using retrograde perfusion of the heart with heparin to displace coronary LPL, we found significantly elevated luminal LPL activity after diabetes.13,15,20,21 We determined that the increased enzyme at the vascular lumen is a consequence of transfer of enzyme from the cardiomyocyte cell surface to the apical side of the endothelial cell. Within the myocyte, recruitment of LPL to the cell surface was controlled by stress kinases like AMPK23 and p38 MAPK, which allowed for actin cytoskeleton polymerization, providing the cardiomyocyte with an infrastructure to facilitate LPL movement.18 In the present study, our data demonstrate that after diabetes induced by DZ or STZ, a cytosolic serine-threonine kinase, PKC-µ, otherwise known as PKD, is a key modulator of LPL vesicular trafficking within the cardiomyocyte.
Heat shock proteins (Hsps), also called stress proteins, are molecular chaperones that assist in protein folding, proper protein conformation, and targeting of proteins to degradative pathways.32,33 Additionally, these stress proteins have been implicated in inhibiting cell death by multiple mechanisms including a direct interaction with cytochrome C and protein kinase C.29,34 Recently, we have shown that Hsp can also affect cardiac metabolism by controlling the movement of cardiac LPL.18 After diabetes, activation of cardiac AMPK and p38 MAPK, by a host of likely mechanisms (including the direct effects of FA,18 nitric oxide mediated cytotoxicity35 and augmentation of superoxide radicals,35 and altered substrate utilization30), facilitated Hsp25 phosphorylation. This allowed actin monomers to be released from Hsp25 to self-associate to form fibrillar actin, an infrastructure that allows LPL to traffic to the cardiomyocyte surface.18 In the current study, we tested whether Hsp25 can also affect PKD, an important kinase that regulates fission of vesicles from the golgi membrane.27 We demonstrate that with phosphorylation of Hsp25, its association with PKC is reduced, enabling PKC phosphorylation and activation. As PKCs (, 
, 
, 
) can directly associate with the pleckstrin homology domain of PKD, allowing for its phosphorylation and activation,36 we determined the interaction between PKC and PKD. Interestingly, after DZ and phosphorylation of PKC, its interaction with PKD increased, facilitating phosphorylation and activation of the later kinase. As the increase in luminal LPL activity was closely associated to the robust phosphorylation of PKD, and as rottlerin, a PKC inhibitor prevented PKD phosphorylation and the subsequent increase in LPL, our data suggest that after diabetes, PKD is a key player responsible for fission of LPL vesicles for eventual transport to the cardiomyocyte cell surface. It should be noted that other studies have also reported an important contribution of PKCs toward LPL secretion in macrophages and adipocytes.37–39
Diabetes is known to activate a number of PKC isoforms.40,41 We attempted to activate PKC by duplicating the plasma concentrations of glucose and FA observed after DZ, and study its influence on cardiac LPL. Control myocytes were incubated with 20 mmol/L glucose and 1.5 mmol/L PA. Although high glucose or PA by themselves had no influence on myocyte LPL, their combination induced a robust increase in myocyte cell surface LPL activity. Given that in the presence of high glucose, unsaturated FA like oleic cid build up as TG whereas saturated FA like PA are diverted toward 1,2-DAG,42 whose downstream signaling includes activation of the PKC super family of enzymes,41,43 we measured levels of this lipid intermediate and report a 1.4-fold increase in myocytes treated with high Glu+PA. Interestingly, similar to DZ, the increase in LPL in myocytes treated with high Glu+PA closely mirrored the increase in phosphorylation of PKC and PKD. The zinc-finger domain of PKD is known to interact with transgolgi membranes, allowing for fission of vesicles.27,44 In addition, activation of PKD is also suggested to promote recruitment of VAMP,28 which helps with vesicle exocytosis and movement along the actin filament network to reach the cell surface. As silencing of PKD prevented the ability of high Glu+PA to increase cell surface LPL, our data suggest that by increasing DAG and promoting activation PKC, PKD is the eventual trigger that enables the cardiomyocyte LPL secretory pathway to turn on.
An alternate strategy to activate PKC is to use PMA, a DAG mimetic that is known to phosphorylate PKC.41,45 Interestingly, in cardiomyocytes, we were unable to observe activation of PKC by PMA, an observation that was previously reported.45 In this setting, PMA was also unable to affect PKD. Given the observation that Hsp25 can prevent activation of PKC through a direct interaction,29 we knocked down Hsp25 using siRNA. In myocytes in which Hsp25 was silenced, PKC and PKD phosphorylation increased, and so did LPL activity. Interestingly, when these myocytes were now exposed to PMA, there was a further phosphorylation of PKC, an appreciable association between PKC and PKD, and a vigorous activation of PKD. As these cells also demonstrated an additional increase in cell surface LPL activity, and as a mutant form of PKC prevented PKD activation and increase in LPL activity observed with high glucose and palmitic acid, our data imply that after diabetes, PKD control of cardiomyocyte LPL activity requires dissociation of Hsp25 from PKC, activation of PKC by DAG, association between PKC and PKD, and vesicular transport of LPL.
In summary, after diabetes, when cardiac glucose utilization is impaired, the heart undergoes metabolic transformation wherein it switches energy production to exclusive β-oxidation of FA. One way by which this process is made possible is through amplification of coronary LPL, thereby allowing uninterrupted FA supply to the diabetic heart. Recruitment of LPL to the cardiomyocyte cell surface and eventually the vascular lumen could represent an immediate compensatory response by the heart to guarantee FA supply. The mechanism underlying this process embraces myocyte increase in actin cytoskeleton polymerization (through an AMPK/p38 MAPK pathway)18 and PKD control of LPL vesicle formation and movement (Figure 8C). Increasing FA uptake through overexpression of cardiac human LPL46 or fatty acid transport protein,47 or augmenting FA oxidation through overexpression of cardiac PPAR-
48 or long-chain acyl CoA synthase,49 results in a cardiac phenotype resembling diabetic cardiomyopathy. Thus, results from the present study could help in restricting or slowing cardiac LPL translocation and could lead to strategies that overcome contractile dysfunction after diabetes.
Limitations of the Study
One limitation of this and other studies4,50–54 is that when examining the lipotoxic effects of palmitic acid on the heart, most studies have used in vitro incubations with 1 to 1.5 mmol/L PA to duplicate the plasma concentration of total FFA observed with diabetes. Given that albumin-bound PA only makes up a fraction of the total plasma FFA, the concentration of PA used may be higher than the actual circulating amount bound to albumin. However, it should be noted that FA derived from the albumin bound fraction does not account for all of the FA provided to the heart. Thus, other physiologically relevant sources like hydrolysis of lipoproteins by cardiac LPL, which has a selective affinity toward palmitic acid containing lipoproteins (47.5% of total fatty acids released),55 also play some role in the provision of PA. This is particularly important as: (1) LPL increases in the DZ diabetic heart, (2) the molar concentrations of FA in lipoproteins are approximately 10-fold higher than that of FA bound to albumin,7 and (3) circulating plasma TG concentrations increase after DZ. As intracellular TG and membrane phospholipids are also potential sources of PA, a true measure of the effects of PA and glucose on cardiac LPL would only be possible if all of these sources of PA are determined after diabetes induced by DZ.
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Acknowledgments |
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The technical expertise of Roger Dyer is gratefully acknowledged.
Sources of Funding
The studies described in this article were supported by an operating grant from the Canadian Diabetes Association.
Disclosures
None.
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Footnotes |
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Original received February 11, 2008; resubmission received May 1, 2008; revised resubmission received June 16, 2008; accepted June 17, 2008.
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