Vascular smooth muscle metabolism and pyruvate dehydrogenase
Metadata[+] Show full item record
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] In dyslipidemic states, most muscle types preferentially utilize fatty acids rather then glucose largely due to modulation of the pyruvate dehydrogenase complex (PDH) activity by pyruvate dehydrogenase kinase (PDK) (54). We have previously shown that vascular smooth muscle (VSM) does not exhibit a decrease in glucose utilization during exposure to increased levels of either short or long chain fatty acids (2, 3). In order to determine if the metabolic inflexibility of VSM may be due to differences in the PDH regulatory mechanisms compared to other muscles, we examined the effects of the PDK inhibitor dichloroacetate (DCA) and the PDP stimulator D-chiro-inositol (DCI) on glucose utilization and lactate production in hog carotid artery (HCA). We also performed western blot analyses of hog skeletal muscle and hog VSM PDK isoforms. In these experiments glycogen stores were allowed to replete overnight at 37[degree sign]C, VSM was isometrically mounted, and incubated for 6 hours in a physiological saline solution containing 5 mM [1- [superscript13]C] glucose and 1 mM [1,2- [superscript13]C] acetate with or without 2 mM DCA or 25 mU/ml insulin and 200 uM DCI. In the presence of DCA, a small but statistically significant (p=0.01) decrease in glucose utilization was observed in VSM. Glucose utilization was significantly increased (p= 0.04) and lactate production was decreased (p= 0.06) in the presence of insulin and DCI. [superscript13]C-NMR analysis of glutamate in these tissues also showed that glucose oxidation was significantly increased (p=0.03). When experiments were repeated using 0.1 mM [1,2[superscript13]C] acetate, glucose utilization was significantly increased (p=0.0001) and lactate production was decreased (p=0.08) in non-contracted HCA in the presence of insulin and DCI. In contracted HCA, glucose utilization was significantly increased (p=0.001). Western blot analyses revealed that there is 2.8 fold more PDK3 and 3.2 fold less PDK2 in VSM compared to skeletal muscle. The presence of PDK3 and the relative insensitivity of HCA to DCA suggests that the PDK isoforms present in VSM may contribute to the metabolic inflexibility of this tissue. Furthermore, the ability of VSM to increase glucose utilization via PDP stimulation by DCI and insulin suggest that the PDH complex in VSM can be manipulated. Therefore, we conclude that PDH in VSM is chronically inhibited by the presence of PDK-3 and the inhibition of PDH may contribute to the metabolic inflexibility of VSM during dyslipidemia, potentially making VSM susceptible to lipotoxicity and atherosclerosis.
Access is limited to the campuses of the University of Missouri.