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Macrophage migration inhibitory factor in hypothalamic paraventricular nucleus neurons decreases blood pressure in spontaneously hypertensive rats

Hongwei Li^*,1, Yongxin Gao^*,1, Yanfei Qi, Michael J. Katovich, Nan Jiang^*, Leah N. Braseth^*, Deborah A. Scheuer^*, Peng Shi^* and Colin Sumners^*,2

^* Department of Physiology and Functional Genomics and McKnight Brain Institute and

Department of Pharmacodynamics, University of Florida, Gainesville, Florida, USA

²Correspondence: Dept. of Physiology and Functional Genomics, College of Medicine, Box 100274, 1600 SW Archer Rd., University of Florida, Gainesville, FL 32610-0274, USA. E-mail: csumners{at}ufl.edu

Macrophage migration inhibitory factor (MIF) expression is increased by angiotensin II (Ang II) within paraventricular nucleus (PVN) neurons of normotensive rats and acts via its intrinsic thiol protein oxidoreductase (TPOR) to counterregulate the central nervous system-mediated pressor action of Ang II. Considering that the PVN-mediated actions of Ang II are enhanced in spontaneously hypertensive rats (SHRs) and contribute to the development of hypertension in these animals, we investigated this MIF regulatory mechanism in SHRs. Here, we have demonstrated that Ang II failed to increase MIF protein expression in the PVN of SHRs. Furthermore, although basal levels of MIF protein and mRNA were similar in the PVN of SHRs and normotensive rats, immunostaining revealed that MIF was either absent from or diminished in PVN neurons of SHRs. AAV2-mediated increases in MIF expression within PVN neurons of young (8 wk old) SHRs produced a chronic attenuation of hypertension and cardiac hypertrophy. However, similar AAV2-mediated transduction of [C60S]-MIF, which lacks TPOR activity, did not alter the development of hypertension or cardiac hypertrophy in SHRs. Collectively, these findings suggest that a lack of MIF expression within PVN neurons contributes to the development of hypertension and cardiac hypertrophy in SHRs.—Li, H., Gao, Y., Qi, Y., Katovich, M. J., Jiang, N., Braseth, L. N., Scheuer, D. A., Shi, P., Sumners, C. Macrophage migration inhibitory factor in hypothalamic paraventricular nucleus neurons decreases blood pressure in spontaneously hypertensive rats.

Key Words: angiotensin II • thiol-protein oxidoreductase • hypertension