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, L. Séress, J. Hamar, K. Hideg, Andras Balogh, F. Gallyas, B. Sümegi, K. Tóth, R. Halmosi

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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 - 2014

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2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one
Quinazolines
Inbred SHR Rats
Blood Vessels
Hypertension
Oxidative Stress
Aorta
Cell Death
Phosphotransferases
Dual Specificity Phosphatase 1
Blood Pressure
Vascular Stiffness
Cell Nucleus Active Transport
Phosphatidylinositol 3-Kinases
Tail
Wistar Rats
Electron Microscopy
Transcription Factors
Collagen
Therapeutics

Keywords

  • PARP-inhibition
  • Spontaneously hypertensive rat
  • Vascular remodeling

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

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title = "A quinazoline-derivative compound with PARP inhibitory effect suppresses hypertension-induced vascular alterations in spontaneously hypertensive rats",
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.",
keywords = "PARP-inhibition, Spontaneously hypertensive rat, Vascular remodeling",
author = "Klara Magyar and Laszlo Deres and Krisztian Eros and Kitti Bruszt and L. S{\'e}ress and J. Hamar and K. Hideg and Andras Balogh and F. Gallyas and B. S{\"u}megi and K. T{\'o}th and R. Halmosi",
year = "2014",
doi = "10.1016/j.bbadis.2014.03.008",
language = "English",
volume = "1842",
pages = "935--944",
journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",
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TY - JOUR

T1 - A quinazoline-derivative compound with PARP inhibitory effect suppresses hypertension-induced vascular alterations in spontaneously hypertensive rats

AU - Magyar, Klara

AU - Deres, Laszlo

AU - Eros, Krisztian

AU - Bruszt, Kitti

AU - Séress, L.

AU - Hamar, J.

AU - Hideg, K.

AU - Balogh, Andras

AU - Gallyas, F.

AU - Sümegi, B.

AU - Tóth, K.

AU - Halmosi, R.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - PARP-inhibition

KW - Spontaneously hypertensive rat

KW - Vascular remodeling

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