Research Article: Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats

Date Published: March 24, 2017

Publisher: Public Library of Science

Author(s): Krisztian Eros, Klara Magyar, Laszlo Deres, Arpad Skazel, Adam Riba, Zoltan Vamos, Tamas Kalai, Ferenc Gallyas, Balazs Sumegi, Kalman Toth, Robert Halmosi, Michael Bader.


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.

Partial Text

Hypertension is one of the most important risk factors of cardiovascular diseases and also contributes to cognitive impairments via vascular alterations [1–3] and oxidative damage of neuronal tissue [4, 5]. Compromised cellular homeostasis of reactive oxygen (ROS) and nitrogen species (RNS) in vascular components are considered as causative factors in chronic hypertension and also mediate its detrimental effects on supplied tissues [6].

Hypertension in brain enhances oxidative stress, via activation of MAP kinases and cyclooxygenase (COX), elevated NO production and increased expression of Nox-2 (NADPH oxidase) [48, 49]. These processes lead to microglia activation, neuroinflammation and cell death [50]. Here we raise the possibility in which inhibition of PARP-1 could be beneficial in this scenario and this hypothesis was tested in SHR animals on the hypertension induced oxidative damage of carotid vessels and neuronal tissue. We observed structural remodeling of carotid arteries in hypertensive animals, characterized by a marked thickening of vascular wall (Fig 1B) and fibrotic tissue accumulation (Fig 1F and 1G). These processes, with an elevated inflammatory status may contribute to the vasomotor alterations seen by dilation properties of CCA rings (Fig 1C and 1D) in the SHR groups. Also, augmented oxidative stress of carotid walls (Fig 1E) and dorsal hippocampus (Fig 3B and 3C) was apparent in animals with chronic hypertension, underlined by the accumulation of nitrogen peroxide byproducts in these tissues.




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