Hepatic ischemia/reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R, and the roles of mitochondria, and the Nrf2/ heme oxygenase-1 (HO-1) system. Wild type, Hmox1-/- or Nrf2-/- mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. HepG2 cells were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2 specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury, and mitochondrial dysfunction. Cilostazol reduced the serum levels of ALT, TNF-α and liver myeloperoxidase content relative to control I/R-treated mice. In cultured HepG2 cells, cilostazol increased the expression of HO-1 and markers of mitochondrial biogenesis, PGC-1α, NRF-1 and TFAM, induced the mitochondrial proteins COX III, and COX IV, and increased mtDNA and mitochondria content. Pre-treatment of HepG2 cells with ZnPP inhibited cilostazol-induced PGC-1α, NRF-1 and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild type mice, but not in Hmox1-/- or Nrf2-/- mice, and failed to protect against liver injury in Nrf2-/- mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2 and HO-1-dependent pathway.
- mitochondrial biogenesis
- Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology