Intermittent Hypoxia Up-Regulates CCL2, RETN, and TNFα mRNAs in Adipocytes via Down-regulation of miR-452

Abstract

Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for insulin resistance. Recently, IH is considered to independently cause adipose tissue inflammation/dysfunction, leading to worsening insulin resistance; however, the detailed mechanism remains unknown. We exposed mouse 3T3-L1 and human SW872 adipocytes to experimental IH or normoxia for 24 h, and analyzed mRNA expression of several adipokines. We found that the mRNA levels of RETN, TNFα, and CCL2 in SW872 and 3T3-L1 adipocytes were significantly increased by IH, whereas the promoter activities of these genes were not increased. A target mRNA search of microRNA (miR)s revealed that all human mRNAs have a potential target sequence for miR-452. The miR-452 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-452 mimic and non-specific control RNA (miR-452 mimic NC) were introduced into SW872 cells, and the IH-induced up-regulation of the genes was abolished by introduction of the miR-452 mimic but not by the miR-452 mimic NC. These results indicate that IH stress down-regulates the miR-452 in adipocytes, resulting in increased levels of RETN, TNFα, and CCL2 mRNAs, leading to insulin resistance in SAS patients.

Association of Adipocytokines With Carotid Intima Media Thickness and Arterial Stiffness in Obstructive Sleep Apnea Patients

“…Yamamoto et al demonstrated that resistin production in OSA patients can be enhanced by hypoxic stress during sleep and could mediate inflammatory processes (60). An experimental study showed that the mRNA levels of resistin were significantly increased in response to intermittent hypoxia (61). In addition, CIMT is positively correlated with serum resistin levels (56).…”

SMAD4 Overexpression in Patients with Sleep Apnoea May Be Associated with Cardiometabolic Comorbidities

“…The growing interest in the interaction between IH and metabolic dysfunction is collected in a recent review [ 52 ]. In this regard, intermittent hypoxia modulates the pancreatic β cells [ 53 ], upregulates the hepatokines resulting the insulin resistance [ 54 ], exacerbates metabolic effects on diet-induced obesity [ 55 ] and the upregulation the adipokines [ 56 ]. Moreover, the intermittent hypoxia increased the systemic oxidative stress, endothelial dysfunction and rennin-angiotensin system activation augmenting the hypertension progress in animal model [ 57 ].…”

Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury

“…Regarding miR-224, this miR is known for regulating adipocyte differentiation 27 , inflammation 28 , and (micro)vascular quiescence or activation 29 . Also miR-452 has a role in metabolism and inflammation because hyperglycemia regulates miR-452 expression 30 and its adipocyte-specific decrease activates a TNF-α induced inflammatory response 31 . However, more studies are needed to investigate whether these miRs pinpoint adipocyte dysfunction as a co-contributor to microvascular injury in diabetic women with LVDD or HFpEF.…”