Elevated Oxidative Stress and Inflammation in Hypothalamic Paraventricular Nucleus Are Associated With Sympathetic Excitation and Hypertension in Rats Exposed to Chronic Intermittent Hypoxia

Abstract

Obstructive sleep apnea (OSA), characterized by recurrent collapse of the upper airway during sleep leading to chronic intermittent hypoxia (CIH), is an independent risk factor for hypertension. Sympathetic excitation has been shown to play a major role in the pathogenesis of OSA-associated hypertension. Accumulating evidence indicates that oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center, mediate sympathetic excitation in many cardiovascular diseases. Here we tested the hypothesis that CIH elevates oxidative stress and inflammation in the PVN, which might be associated with sympathetic excitation and increased blood pressure in a rat model of CIH that mimics the oxygen profile in patients with OSA. Sprague-Dawley rats were pretreated with intracerebroventricular (ICV) infusion of vehicle or superoxide scavenger tempol, and then exposed to control or CIH for 7 days. Compared with control+vehicle rats, CIH+vehicle rats exhibited increased blood pressure, and increased sympathetic drive as indicated by the blood pressure response to ganglionic blockade and plasma norepinephrine levels. Pretreatment with ICV tempol prevented CIH-induced increases in blood pressure and sympathetic drive. Molecular studies revealed that expression of NAD(P)H oxidase subunits, production of reactive oxygen species, expression of proinflammatory cytokines and neuronal excitation in the PVN were elevated in CIH+vehicle rats, compared with control+vehicle rats, but were normalized or reduced in CIH rat pretreated with ICV tempol. Notably, CIH+vehicle rats also had increased systemic oxidative stress and inflammation, which were not altered by ICV tempol. The results suggest that CIH induces elevated oxidative stress and inflammation in the PVN, which lead to PVN neuronal excitation and are associated with sympathetic excitation and increased blood pressure. Central oxidative stress and inflammation may be novel targets for the prevention and treatment of hypertension in patients with OSA.

Prebiotic administration modulates gut microbiota and faecal short-chain fatty acid concentrations but does not prevent chronic intermittent hypoxia-induced apnoea and hypertension in adult rats

“…Our modest CIH paradigm did not increase plasma or brainstem pro-inflammatory cytokines, consistent with other studies showing no difference in systemic pro-inflammatory cytokine concentrations following exposure to CIH [ 80 , 84 ]. However, others have displayed neuro- and systemic inflammation as a result of severe CIH exposure [ 20 , [84] , [85] , [86] ]. Differences are likely due to pattern, duration and intensity of CIH exposure.…”

“…However, exposure to CIH elicits cardiorespiratory and autonomic disturbances in guinea-pigs with hypoxia-insensitive carotid bodies [ 13 , 14 ], revealing that sites beyond the carotid bodies can contribute to the manifestation of CIH-induced cardiorespiratory and autonomic disturbances. It is known that CIH-induced plasticity also occurs at other key sites of the cardiorespiratory control circuit, including the nucleus tractus solitarius (NTS), pre-Bötzinger complex, ponto-medullary network and paraventricular nucleus of the hypothalamus [15] , [16] , [17] , [18] , [19] , [20] . More recently, studies have described effects of CIH on other peripheral sites including the gut microbiota [ 12 , 14 , [21] , [22] , [23] , [24] , [25] , [26] ].…”

HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia

“…Overactive brain local renin-angiotensin system (RAS), oxidative stress, and neuroinflammation in the brainstem cardioregulatory centers rostral ventrolateral medulla (RVLM) and other brain regions such as hypothalamic paraventricular nucleus (PVN) are the key factors in augmenting sympathetic activity [6,7]. Furthermore, it has been well established that sympathetic excitation and increased blood pressure (BP) are resulted from elevated oxidative stress and inflammation in the PVN, which excite PVN neurons [8].…”

The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome

“…Due to the advances in diagnostic equipment and evolvement of diagnostic criteria, the prevalence of OSAS in the population has increased with time [ 3 ]. The adverse medical conditions associated with OSAS include cardiovascular disease [ 4 – 6 ] (coronary artery disease, heart failure, atrial fibrillation, hypertension, and stroke), metabolic dysfunction [ 7 , 8 ] (dyslipidemia and diabetes mellitus), and neurocognitive impairment [ 9 , 10 ]. Recently, cognitive impairment has been proven to be an important complication of OSAS and deserves enough attention.…”