Klara Magyar1, Laszlo Deres1, Krisztian Eros1, Kitti Bruszt1, Laszlo Seress2, Janos Hamar3, Kalman Hideg4, Andras Balogh5, Ferenc Gallyas6, Balazs Sumegi7, Kalman Toth8, Robert Halmosi9. 1. 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary. 2. Central Electron Microscope Laboratory, University of Pecs, Medical School, Pecs, Hungary. 3. Department of Pathophysiology and Gerontology, University of Pecs, Medical School, Pecs, Hungary. 4. Department of Organic and Pharmacological Chemistry, University of Pecs, Medical School, Pecs, Hungary. 5. Department of Medical Biology, University of Pecs, Medical School, Pecs, Hungary. 6. Department of Biochemistry and Medical Chemistry, University of Pecs, Medical School, Pecs, Hungary; MTA-PTE, Nuclear and Mitochondrial Interactions Research Group, Pecs, Hungary. 7. Department of Biochemistry and Medical Chemistry, University of Pecs, Medical School, Pecs, Hungary; MTA-PTE, Nuclear and Mitochondrial Interactions Research Group, Pecs, Hungary; Szentagothai Janos Research Center, University of Pecs, Medical School, Pecs, Hungary. 8. 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary; MTA-PTE, Nuclear and Mitochondrial Interactions Research Group, Pecs, Hungary. 9. 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary; Szentagothai Janos Research Center, University of Pecs, Medical School, Pecs, Hungary. Electronic address: halmosi.robert@pte.hu.
Abstract
AIMS: Oxidative stress and neurohumoral factors play important role in the development of hypertension-induced vascular remodeling, likely by disregulating kinase cascades and transcription factors. Oxidative stress activates poly(ADP-ribose)-polymerase (PARP-1), which promotes inflammation and cell death. We assumed that inhibition of PARP-1 reduces the hypertension-induced adverse vascular changes. This hypothesis was tested in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Ten-week-old male SHRs and wild-type rats received or not 5mg/kg/day L-2286 (a water-soluble PARP-inhibitor) for 32 weeks, then morphological and functional parameters were determined in their aortas. L-2286 did not affect the blood pressure in any of the animal groups measured with tail-cuff method. Arterial stiffness index increased in untreated SHRs compared to untreated Wistar rats, which was attenuated by L-2286 treatment. Electron and light microscopy of aortas showed prominent collagen deposition, elevation of oxidative stress markers and increased PARP activity in SHR, which were attenuated by PARP-inhibition. L-2286 treatment decreased also the hypertension-activated mitochondrial cell death pathway, characterized by the nuclear translocation of AIF. Hypertension activated all three branches of MAP-kinases. L-2286 attenuated these changes by inducing the expression of MAPK phosphatase-1 and by activating the cytoprotective PI-3-kinase/Akt pathway. Hypertension activated nuclear factor-kappaB, which was prevented by PARP-inhibition via activating its nuclear export. CONCLUSION: PARP-inhibition has significant vasoprotective effects against hypertension-induced vascular remodeling. Therefore, PARP-1 can be a novel therapeutic drug target for preventing hypertension-induced vascular remodeling in a group of patients, in whom lowering the blood pressure to optimal range is harmful or causes intolerable side effects.
AIMS: Oxidative stress and neurohumoral factors play important role in the development of hypertension-induced vascular remodeling, likely by disregulating kinase cascades and transcription factors. Oxidative stress activates poly(ADP-ribose)-polymerase (PARP-1), which promotes inflammation and cell death. We assumed that inhibition of PARP-1 reduces the hypertension-induced adverse vascular changes. This hypothesis was tested in spontaneously hypertensiverats (SHR). METHODS AND RESULTS: Ten-week-old male SHRs and wild-type rats received or not 5mg/kg/day L-2286 (a water-soluble PARP-inhibitor) for 32 weeks, then morphological and functional parameters were determined in their aortas. L-2286 did not affect the blood pressure in any of the animal groups measured with tail-cuff method. Arterial stiffness index increased in untreated SHRs compared to untreated Wistar rats, which was attenuated by L-2286 treatment. Electron and light microscopy of aortas showed prominent collagen deposition, elevation of oxidative stress markers and increased PARP activity in SHR, which were attenuated by PARP-inhibition. L-2286 treatment decreased also the hypertension-activated mitochondrial cell death pathway, characterized by the nuclear translocation of AIF. Hypertension activated all three branches of MAP-kinases. L-2286 attenuated these changes by inducing the expression of MAPK phosphatase-1 and by activating the cytoprotective PI-3-kinase/Akt pathway. Hypertension activated nuclear factor-kappaB, which was prevented by PARP-inhibition via activating its nuclear export. CONCLUSION: PARP-inhibition has significant vasoprotective effects against hypertension-induced vascular remodeling. Therefore, PARP-1 can be a novel therapeutic drug target for preventing hypertension-induced vascular remodeling in a group of patients, in whom lowering the blood pressure to optimal range is harmful or causes intolerable side effects.