title: A quinazoline-derivative compound with PARP inhibitory effect suppresses hypertension-induced vascular alterations in spontaneously hypertensive rats.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Klara
authors.initials: K
authors.lastname: Magyar
authors.affiliation: 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Deres
authors.affiliation: 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Eros
authors.affiliation: 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Kitti
authors.initials: K
authors.lastname: Bruszt
authors.affiliation: Central Electron Microscope Laboratory, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Seress
authors.affiliation: Department of Pathophysiology and Gerontology, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Janos
authors.initials: J
authors.lastname: Hamar
authors.affiliation: Department of Organic and Pharmacological Chemistry, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Kalman
authors.initials: K
authors.lastname: Hideg
authors.affiliation: Department of Medical Biology, University of Pecs, Medical School, Pecs, Hungary.
authors.forename: Andras
authors.initials: A
authors.lastname: Balogh
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Medical School, Pecs, Hungary; MTA-PTE, Nuclear and Mitochondrial Interactions Research Group, Pecs, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.affiliation: 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.
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.affiliation: 1st Department of Medicine, University of Pecs, Medical School, Pecs, Hungary; MTA-PTE, Nuclear and Mitochondrial Interactions Research Group, Pecs, Hungary.
authors.forename: Kalman
authors.initials: K
authors.lastname: Toth
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Halmosi
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C505456:2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one; D016328:NF-kappa B; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D003094:Collagen; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: PARP-inhibition; Spontaneously hypertensive rat; Vascular remodeling