Thorac Cardiovasc Surg 2015; 63 - OP224
DOI: 10.1055/s-0035-1544476

DCA Alleviates Myointima Formation via a Redox-sensitive c-myc Pathway

T. Deuse 1, D. Wang 2, J. P. Bolanos 3, X. Hua 2, J. M. Spin 4, M. Stubbendorff 2, X. Hu 2, H. Reichenspurner 1, R. C. Robbins 5, P.S. Tsao 4, 6, S. Schrepfer 2, 7
  • 1Universitäres Herzzentrum Hamburg, Herz- und Gefäßchirurgie, Hamburg, Germany
  • 2Universitäres Herzzentrum Hamburg, TSI Lab, Hamburg, Germany
  • 3University of Salamanca, Institute of Functional Biology and Genomics, Salamanca, Spain
  • 4Stanford University, Cardiovascular Medicine, Stanford, United States
  • 5Stanford University, CT Surgery, Stanford, United States
  • 6Stanford University, Veterans Administration Palo Alto Health Care Services, Stanford, United States
  • 7Department of Cardiothoracic Surgery, Stanford University, Stanford, United States

Background: Myointimal hyperplasia (MH) is a severe pathological condition that is characterized by excessive vascular smooth muscle cell (SMC) proliferation and results in progressive luminal narrowing of affected arteries, promoting proliferative vascular diseases like coronary and peripheral artery disease.

Methods and Results: We recently developed a novel humanized in vivo model for MH where freshly isolated human mammary arteries undergo balloon-injury and are implanted into the aortic position of RNU rats (Deuse T. Nature 2014;509:641–644). Utilizing this model, we show that during the development of MH, SMCs exhibit mitochondrial membrane (ΔΨm) hyperpolarization and acquire a temporary state with high proliferative activity and resistance to apoptosis. This SMC condition, which we believe is the pathophysiological basis of MH, coincided with vessel inflammation and could be mimicked by incubation of SMCs with PDGF in vitro. Mechanistically, we show that concomitant to ΔΨm hyperpolarization in injured arteries or in PDGF-stimulated SMCs, mitochondrial superoxide (mO2-) was suppressed. PDGF-induced ΔΨm hyperpolarization depended on a mO2-controlled redox-sensitive pathway involving p53 and c-myc and provoked apoptosis resistance. In this context, the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK)2 was identified as a key regulatory protein for both mO2- and ΔΨm. PDK2 activation proved necessary for relevant injury-induced myointima formation in arteries. Pharmacologic PDK2 blockade with dichloroacetate (DCA) or lentiviral PDK2 knock-down prevented mO2- suppression, ΔΨm hyperpolarization and facilitated apoptosis. mO2- and ΔΨm directly correlated with pyruvate dehydrogenase PDH activity. In 5 different animal models, oral DCA reduced MH. In contrast to several commonly used antiproliferative drugs, DCA did not prevent vessel re-endothelialization in vivo.

Conclusion: Our results show a functional role of a redox-sensitive c-myc pathway for the regulation of ΔΨm in SMCs and the development of MH in balloon-injured arteries. Targeting myointimal ΔΨm with DCA and alleviating apoptosis resistance is a novel, not yet utilized strategy for the prevention of proliferative vascular diseases.