Redox-active DJ-1 sustains brainstem cardiovascular regulation via maintenance of mitochondrial function during mevinphos intoxication

Abstract

DJ-1 (also known as PARK7) is a redox-active protein that protects against oxidative stress. This study evaluated the hypothesis that DJ-1 sustains brainstem cardiovascular regulation via maintaining mitochondrial function in the rostral ventrolateral medulla (RVLM), a brainstem site known to maintain blood pressure and sympathetic vasomotor tone, during cardiovascular depression elicited by the organophosphate insecticide mevinphos. In Sprague–Dawley rats, intravenous administration of mevinphos (640 μg kg−1) resulted in progressive hypotension, accompanied by an increase (Phase I) followed by a decrease (Phase II) of an experimental index for spontaneous baroreflex-mediated sympathetic vasomotor tone, alongside elevation in mitochondrial superoxide levels in the RVLM. There was concurrent activation of DJ-1 induced by oxidative stress in the RVLM, which was causally and temporally related to translocation of DJ-1 to mitochondria, reduction in mitochondrial membrane potential, increase in cytosolic apoptosis-inducing factor level, and apoptotic cell death in this brainstem site. Loss-of-function by immunoneutralization of DJ-1 in the RVLM significantly exacerbated those biochemical and cellular events, enhanced the progressive hypotension, diminished the increased and augmented the decreased spontaneous baroreflex-mediated sympathetic vasomotor tone respectively during Phases I and II, and heightened lethality during mevinphos intoxication. We conclude that DJ-1 in the RVLM sustains brainstem cardiovascular regulation induced by mevinphos via maintaining mitochondrial function.