Protein kinase D is a key regulator of cardiomyocyte lipoprotein lipase secretion after diabetes

作者：Kim Min Suk; Wang Fang; Puthanveetil Prasanth; Kewalramani Girish; Hosseini Beheshti Elham; Ng Natalie; Wang Yanni; Kumar Ujendra; Innis Sheila; Proud Christopher G; Abrahani Ashraf; Rodrigues Brian^*

来源：Circulation Research, 2008, 103(3): 252-260.

DOI：10.1161/CIRCRESAHA.108.178681

• heat shock protein
• protein kinase C
• hyperglycemia
• hyperlipidemia
• vesicles

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 delta, 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 delta 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 delta, 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 delta was expressed, high Glu delta PA were incapable of increasing LPL. Moreover, silencing of cardiomyocyte Hsp25 allowed phorbol 12-myristate 13-acetate to elicit a significant phosphorylation of PKC delta, an appreciable association between PKC delta 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 delta, association between PKC delta 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.

• 出版日期2008-8-1