Thorac Cardiovasc Surg 2012; 60 - V43
DOI: 10.1055/s-0031-1297433

Pyruvate dehydrogenase kinase 2 controls the development of intimal hyperplasia

T Deuse 1, X Hua 1, F Laenger 2, T Gossler 1, M Stubbendorff 1, A Rakovic 3, C Klein 3, G Sutendra 4, P Dromparis 4, L Maegdefessel 5, PS Tsao 5, J Velden 6, H Reichenspurner 1, RC Robbins 7, F Haddad 7, E Michelakis 4, S Schrepfer 1, 7
  • 1University Heart Center Hamburg, TSI-Lab, Hamburg, Germany
  • 2University of Hannover, Pathology, Hannover, Germany
  • 3University of Luebeck, Department of Neurology, Luebeck, Germany
  • 4University of Alberta, CV Medicine, Edmonton, Canada
  • 5Stanford University, CV Medicine, Stanford, United States
  • 6University Hospital of Hamburg-Eppendorf, Pathology, Hamburg, Germany
  • 7Stanford University, CT Surgery, Stanford, United States

Aims: Intimal hyperplasia (IH) and restenosis are characterized by aberrant smooth muscle cell (SMC) proliferation. We hypothesized that SMC may utilize molecular pro-survival mechanisms involving metabolic modulation known from autonomous cancer growth. Mitochondrial metabolism and its regulatory key enzyme pyruvate dehydrogenase kinase (PDK) 2, catalyzing the phosphorylation of pyruvate dehydrogenase (PDH) and thus regulating the flux of pyruvate into the mitochondria, were investigated during SMC proliferation and the development of human IH.

Methods and results: A novel human IH model was established in which balloon-injured human internal mammary arteries (hMA) were transplanted into the abdominal aortic position of nude rats. IH rapidly developed over 21 days and was morphologically and in immunohistochemistry identical to the neointima of human coronary arteries. Over 21 days, we found increased proliferative and decreased apoptotic activity within the IH lesion and luminal obliteration progressed to approx. 60%. Tissue PDK2 expression was significantlyelevatedandPDH was inhibited. Beyond 21 days, PDK2 and PDH activity normalized and there was no relevant further IH progression. PDGF was markedly elevated in the animal serum during neointima formation. Activation of SMC in vitro with PDGF caused increased PDK2 activity via both PI3K/Akt and Ras/Raf/Erkpathways. We observed an increase of the mitochondrial membrane potential (ΔΨm), a decreased release of mitochondrial reactive oxygen species (mROS), as well as enhanced cell proliferation. PDK2 inhibition using dichloroacetate(DCA) or PDK2 shRNA prevented PDGF-induced mitochondrial hyperpolarization and SMC proliferation. In vivo, oral DCA treatment of rats or pre-implant PDK2 shRNA-transduction of the hMAs prevented the injury-induced increase of SMC proliferation and significantly decreased IH development.

Conclusions: PDK2 is the link between PDGF downstream pathways and mitochondrial metabolic modulation and its activation facilitates SMC proliferation. Pharmacological or genetic inhibition of PDK2 in SMC attenuates PDGF-induced increase inΔΨm, cell proliferation and the development of human IH. PDK2 may be a novel target for the prevention of restenosis.