Tohoku J. Exp. Med., 2023 February, 259(2)

Minocycline and Pyrrolidine Dithiocarbamate Attenuate Hypertension via Suppressing Activation of Microglia in the Hypothalamic Paraventricular Nucleus

Xiao-Jing Liu,¹ Xiao-Jing Yu,² Yu-Kun Su,³ Jin-An Qiao,^2,4 Yao-Jun Sun,⁵ Xiao-Jie Bai,⁵ Nana Zhang,⁶ Hui-Yu Yang,⁷ Li-Xi Yin,⁸ Yu-Ming Kang² and Zhi-Ming Yang⁷

¹The Second Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
²Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi’an, Shaanxi, China
³Hemodialysis Center, Shanxi Second People’s Hospital, Taiyuan, Shanxi, China
⁴Institute of Pediatric Diseases, Xi’an Children’s Hospital, Xi’an, Shaanxi, China
⁵Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, China
⁶Department of Hypertension, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
⁷Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
⁸Basic Medical College of Shanxi Medical University, Taiyuan, Shanxi, China

Proinflammatory cytokines, reactive oxygen species and imbalance of neurotransmitters are involved in the pathophysiology of angiotensin II-induced hypertension. The hypothalamic paraventricular nucleus (PVN) plays a vital role in hypertension. Evidences show that microglia are activated and release proinflammatory cytokines in angiocardiopathy. We hypothesized that angiotensin II induces PVN microglial activation, and the activated PVN microglia release proinflammatory cytokines and cause oxidative stress through nuclear factor-kappa B (NF-κB) pathway, which contributes to sympathetic overactivity and hypertension. Male Sprague-Dawley rats (weight 275-300 g) were infused with angiotensin II to induce hypertension. Then, rats were treated with bilateral PVN infusion of microglial activation inhibitor minocycline, NF-κB activation inhibitor pyrrolidine dithiocarbamate or vehicle for 4 weeks. When compared to control groups, angiotensin II-induced hypertensive rats had higher mean arterial pressure, PVN proinflammatory cytokines, and imbalance of neurotransmitters, accompanied with PVN activated microglia. These rats also had more PVN gp91^phox (source of reactive oxygen species production), and NF-κB p65. Bilateral PVN infusion of minocycline or pyrrolidine dithiocarbamate partly or completely ameliorated these changes. This study indicates that angiotensin II-induced hypertensive rats have more activated microglia in PVN, and activated PVN microglia release proinflammatory cytokines and result in oxidative stress, which contributes to sympathoexcitation and hypertensive response. Suppression of activated PVN microglia by minocycline or pyrrolidine dithiocarbamate attenuates inflammation and oxidative stress, and improves angiotensin II-induced hypertension, which indicates that activated microglia promote hypertension through activated NF-κB. The findings may offer hypertension new strategies.

Keywords —— hypertension; hypothalamic paraventricular nucleus; microglia; minocycline; pyrrolidine dithiocarbamate

© 2023 Tohoku University Medical Press

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Tohoku J. Exp. Med 2023, 259, 163-172.

Correspondence: Yu-Ming Kang, M.D., Ph.D., Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, No.76 Yanta West Road, Xi’an, Shaanxi 710061, China.

e-mail: ykang@mail.xjtu.edu.cn

Zhi-Ming Yang, Prof., Department of Cardiology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, Shanxi 030001, China.

e-mail: zhimingyang800@sina.com