Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats.
Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP-ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure. 32 weeks of L-2286 treatment attenuated these processes by modulating mitogen activated protein kinase phosphatase-1 cellular levels in carotid arteries. In hypertensive animals, vascular inflammation and endothelial dysfunction was observed by NF-κB nuclear accumulation and impaired vasodilation to acetylcholine, respectively. Pharmacological poly(ADP-ribose)polymerase-1 inhibition interfered in these processes and mitigated Apoptosis Inducing Factor dependent cell death events, thus improved structural and functional alterations of carotid arteries, without affecting blood pressure. Chronic poly(ADP-ribose)polymerase-1 inhibition protected neuronal tissue against oxidative damage, assessed by nitrotyrosine, 4-hydroxinonenal and 8-oxoguanosine immunohistochemistry in the area of Cornu ammonis 1 of the dorsal hippocampus in hypertensive rats. In this area, extensive pyramidal cell loss was also attenuated by treatment with lowered poly(ADP-ribose)polymer formation. It also preserved the structure of fissural arteries and attenuated perivascular white matter lesions and reactive astrogliosis in hypertensive rats. These data support the premise in which chronic poly(ADP-ribose)polymerase-1 inhibition has beneficial effects on hypertension related tissue damage both in vascular tissue and in the hippocampus by altering signaling events, reducing oxidative/nitrosative stress and inflammatory status, without lowering blood pressure.
1st Department of Medicine, Clinical Centre, University of Pecs, Pecs, Baranya, Hungary.|Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.|Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, Pecs, Baranya, Hungary.
Krisztian
K
Eros
1st Department of Medicine, Clinical Centre, University of Pecs, Pecs, Baranya, Hungary.
Klara
K
Magyar
1st Department of Medicine, Clinical Centre, University of Pecs, Pecs, Baranya, Hungary.|Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.
Laszlo
L
Deres
1st Department of Medicine, Clinical Centre, University of Pecs, Pecs, Baranya, Hungary.
Arpad
A
Skazel
1st Department of Medicine, Clinical Centre, University of Pecs, Pecs, Baranya, Hungary.|Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.
Adam
A
Riba
Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.|Department of Pathophysiology and Gerontology, Medical School, University of Pecs, Pecs, Baranya, Hungary.
Zoltan
Z
Vamos
Department of Organic and Pharmacological Chemistry, Medical School, University of Pecs, Pecs, Baranya, Hungary.
Tamas
T
Kalai
Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.|Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, Pecs, Baranya, Hungary.
Ferenc
F
Gallyas
Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.|Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, Pecs, Baranya, Hungary.|MTA-PTE Nuclear and Mitochondrial Interactions Research Group, University of Pecs, Pecs, Baranya, Hungary.
Balazs
B
Sumegi
1st Department of Medicine, Clinical Centre, University of Pecs, Pecs, Baranya, Hungary.|Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.|MTA-PTE Nuclear and Mitochondrial Interactions Research Group, University of Pecs, Pecs, Baranya, Hungary.
Kalman
K
Toth
1st Department of Medicine, Clinical Centre, University of Pecs, Pecs, Baranya, Hungary.|Szentagothai Research Centre, University of Pecs, Pecs, Baranya, Hungary.
Robert
http://orcid.org/0000-0002-6965-7743
R
Halmosi
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D066253:Vascular Remodeling / Q000187:drug effects*
C505456:2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D000071137:Poly (ADP-Ribose) Polymerase-1