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Sleep disorders increase the risk of cardiovascular diseases. However, the underlying mechanisms remain unclear. This study aims to examine the critical role of oxytocin neurons in the paraventricular nucleus (PVN^OXT) in regulating the cardiovascular system and to elucidate potential mechanisms through which sleep disturbance may contribute to cardiovascular diseases. In this study, using an automated sleep deprivation system, mice were given chronic sleep deprivation (cSD) for 7 days, 6 h per day. cSD induced blood transcriptomic alterations accompanied by lower heart rate, higher blood pressure, and elevated cardiac autophagy/apoptosis. Instant optogenetic activation of oxytocin neurons in the paraventricular nucleus (PVN^OXT) provoked heart rate suppression in normal mice, whereas in cSD mice, activation precipitated intermittent cardiac arrest. On the contrary, inhibition of PVN^OXT showed no influence on the cardiovascular system of normal mice, but it attenuated cSD-induced rise in blood pressure. Long-term low-frequency stimulation (LTF) of PVN^OXT decreased neuronal excitability and oxytocin release, effectively reversing cSD-mediated cardiovascular responses. Mechanistically, cSD triggered the upregulation of blood-derived 3-mercaptopyruvate sulfurtransferase (mPST), and a suppression of PVN^OXT postsynaptic activity to a certain extent. The quick and long-term decrease of oxytocin by LTF could lead to feedback inhibition in mPST expression and thus reverse cSD-mediated cardiovascular responses. Altogether, modulation of PVN^OXT could mediate cSD-induced cardiovascular abnormalities without affecting normal mice. Our research provided potential targets and key mechanisms for cardiovascular diseases associated with sleep disorders.