Abstract P339: A Possible Role Of Neuronal Adam17 In The Development Of Hypertension And Related Cognitive Impairment By Altering The Microenvironment

Abstract

Hypertension is one of the most prevalent cardiovascular diseases worldwide and is known to be dominated by the sympathetic nervous system (SNS). Previously, we found that targeting A Disintegrin and Metalloproteinase 17 (ADAM17) in glutamatergic neurons was able to blunt Ang-II-induced excitation of pre-autonomic neurons, and blocked DOCA-salt treatment-induced sympatho-excitation in mice, thereby alleviating their development of hypertension. However, how ADAM17 support the activation of pre-autonomic neurons remains unknown. Beyond the glutamatergic neurons, we found in the current study that microglial activation and increase of pro-inflammatory cytokine levels in the hypothalamus, induced by DOCA-salt treatment, were blunted in those mice with ADAM17 knockout in glutamatergic neurons (A17G; number of CD11b+cells per line: NT+DOCA vs. A17G+DOCA= 11±2 vs. 6±1, P= 0.0017; normalized TNFα level: NT+DOCA vs. A17G+DOCA= 1.00±0.37 vs. 0.67±0.11, P< 0.05; normalized IL-6 level: 1.00±0.32 vs. 0.59±0.20, P< 0.05). Especially, it also reversed DOCA-salt-induced downregulation of Gad67 mRNA expression (NT= 1.00±0.11, NT+DOCA= 0.66±0.12, A17G= 1.02±0.15, A17G+DOCA= 1.67±0.24 fold of change, NT vs. NT+DOCA and A17G vs. A17G+DOCA: P< 0.05), and normalized the decreased level of GABA in hypothalamus (normalized GABA levels: NT= 1.00±0.15, NT+DOCA= 0.84±0.09, A17G+DOCA= 1.09±0.17, NT vs. NT+DOCA: P< 0.05), suggesting that in addition to the effect of ADAM17 on the neuron itself, it might also regulate the SNS through altering the neuronal microenvironment. In L-NAME hypertensive model, though A17G mice showed no improvement in NOS-blockade-induced dysfunction of neuro-vascular coupling (increase of CBF induced by whisker-stimulation: NT vs. A17G= 24.34±11.20 vs. 24.87±15.78 PU%), it did exhibit improved performance in Barnes maze test (latency time: NT vs. A17G= 32.77±19.36 vs. 95.54±59.03 s, P= 0.002), suggesting that ADAM17 in glutamatergic is critical for the process of neuronal damage induced by hypoxia and ischemia, possibly through modulating the homeostasis of neuronal microenvironment.