A quinazoline-derivative compound with PARP inhibitory effect suppresses hypertension-induced vascular alterations in spontaneously hypertensive rats

Klara Magyar, Laszlo Deres, Krisztian Eros, Kitti Bruszt, Laszlo Seress, Janos Hamar, Kalman Hideg, Andras Balogh, Ferenc Gallyas, Balazs Sumegi, Kalman Toth, Robert Halmosi

Research output: Article

14 Citations (Scopus)

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 5. mg/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.

Original languageEnglish
Pages (from-to)935-944
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number7
DOIs
Publication statusPublished - júl. 2014

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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