In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.

Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep. OSA has been shown to be a risk factor for atherosclerosis, but the relation of IHC to the induction or progression of atherosclerosis is not well understood. To dissect the mechanisms involved, we compared atherosclerotic lesion formation in two mouse models, i.e., apolipoprotein E (ApoE) and low density lipoprotein receptor (Ldlr)-deficient mice, with or without IHC exposure. Ten-week-old ApoE^-/- or Ldlr^-/- mice were fed a high-fat diet for 4 or 8 weeks while being exposed to IHC for 10 hours/day or room air (RA) for 24 hours/day. En face lesions of the aorta, aortic arch, and pulmonary artery (PA) were examined. Moreover, 3,3-dimethyl-1-butanol (DMB), an inhibitor of microbial trimethylamine (TMA) production, was used to determine the contribution of TMA-oxide (TMAO) to IHC-induced atherosclerosis. Eight weeks of IHC exposure expedited the formation of atherosclerosis in both the PA and aortic arch of ApoE^-/- mice, but only in the PA of Ldlr^-/- mice (ApoE^-/- PA 8 wk, IHC 35.4 ± 1.9% versus RA 8.0 ± 2.8%, P < 0.01). The atherosclerotic lesions evolved faster and to a more severe extent in ApoE^-/- mice as compared with Ldlr^-/- mice (PA IHC 8 wk, ApoE^-/- 35.4 ± 1.9% versus Ldlr^-/- 8.2 ± 1.5%, P < 0.01). DMB significantly attenuated but did not totally eliminate IHC-induced PA atherosclerosis. Our findings suggest that IHC, a hallmark of OSA, accelerates the progression of atherosclerosis in the aorta and especially in the PA. This process is partly inhibited by DMB, demonstrating that microbial metabolites may serve as therapeutic targets for OSA-induced atherosclerosis.