Abstract
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.
Highlights
Hypertension is one of the most important risk factors of cardiovascular diseases and contributes to cognitive impairments via vascular alterations [1,2,3] and oxidative damage of neuronal tissue [4, 5]
PARP-1 is a coregulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) during inflammatory response, and in this way, its activity contributes to additional ROS accumulation via immunological processes leading to deterioration of endothelial integrity and damage of surrounding tissues [24,25,26,27]
We successfully evaluated important molecular mechanisms of arterial remodeling regarding NF-kB signaling and mitogen activated protein kinases (MAPKs) members activity in the Spontaneously Hypertensive Rats (SHR) model in relation to L-2286 treatment [32]
Summary
Hypertension is one of the most important risk factors of cardiovascular diseases and contributes to cognitive impairments via vascular alterations [1,2,3] and oxidative damage of neuronal tissue [4, 5]. A pro-oxidant state with inflammatory markers in vessels of human patients and animal models precedes the development of elevated blood pressure [7, 9] It conveys detrimental effects, as accumulating ROS reacts with and reduces the bioavailability of nitrogen monoxide (NO)—an important paracrine regulator of vascular tone -, by forming the highly reactive peroxynitrite (ONOO-) [10, 11]. An increased formation of ONOO- in the vicinity of vascular endothelium activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1) [12,13,14,15,16,17] contributing to endothelial damage and dysfunction in various pathologies, including chronic hypertension [17] In this manner, excess ROS production directly and via PARP1 activation, modulates activity of intracellular signaling routes and transcription factors [8, 18, 19]. Excess PARP-1 activity has been shown to modulate stress related signaling routes and initiate a caspase independent form of cell death, termed as parthanatos, in the scenario of myocardial ischemia/reperfusion damage [28] doxorubicin induced cardiac injury [29], hyperglycaemia related oxidative damage and endothelial dysfunction [30], acute septic shock [31] and chronic hypertension induced remodeling of rat aorta [32]
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