No abstract

Thyroid hormone is a critical determinant of cellular metabolism and differentiation. Precise tissue-specific regulation of the active ligand 3,5,3′-triiodothyronine (T3) is achieved by the sequential removal of iodine groups from the thyroid hormone molecule, with type 3 deiodinase (D3) comprising the major inactivating pathway that terminates the action of T3 and prevents activation of the prohormone thyroxine. Using cells endogenously expressing D3, we found that hypoxia induced expression of the D3 gene DIO3 by a hypoxiainducible factor-dependent (HIF-dependent) pathway. D3 activity and mRNA were increased both by hypoxia and by hypoxia mimetics that increase HIF-1. Using ChIP, we found that HIF-1α interacted specifically with the DIO3 promoter, indicating that DIO3 may be a direct transcriptional target of HIF-1. Endogenous D3 activity decreased T3-dependent oxygen consumption in both neuronal and hepatocyte cell lines, suggesting that hypoxia-induced D3 may reduce metabolic rate in hypoxic tissues. Using a rat model of cardiac failure due to RV hypertrophy, we found that HIF-1α and D3 proteins were induced specifically in the hypertrophic myocardium of the RV, creating an anatomically specific reduction in local T3 content and action. These results suggest a mechanism of metabolic regulation during hypoxic-ischemic injury in which HIF-1 reduces local thyroid hormone signaling through induction of D3.

Abstract-We have previously shown that exercise training activates nucleus tractus solitarii (NTS) oxytocinergic projections, resulting in blunted exercise tachycardia. The objective of this study was to determine the effects of hypertension and training on oxytocin (OT) and OT receptor expression in the hypothalamic paraventricular nucleus (PVN) and projection areas (dorsal brain stem [DBS]). Male, normotensive, Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were trained (55% maximal exercise capacity, 3 months) or kept sedentary, and pressure was measured weekly. DBS sections were processed for immunohistochemistry (polyclonal guinea pig anti-OT) or in situ hybridization for OT and OT receptor ( 35 S-oligonucleotide probes). Other groups of rats had brains removed and frozen to isolate the DBS and PVN; samples were processed for OT and OT receptor cDNA reverse transcription-polymerase chain reaction amplification with ␤-actin as the housekeeping gene. Training was equally effective in improving running distance in both groups, with pressure reduction only in SHR (Ϫ10%, PϽ0.05). In trained WKY, baseline bradycardia (PϽ0.05) occurred simultaneously with increased NTS OT immunostaining and mRNA expression (ϩ3.5-fold), without any change in OT receptor mRNA expression. PVN OT mRNA and DBS OT receptor mRNA expressions were significantly lower in SHR versus WKY (Ϫ39% and Ϫ56%, respectively). Training did not alter DBS OT receptor density in the SHR group but increased OT mRNA in both PVN and DBS areas (ϩ78% and ϩ45%, respectively). Our results show a marked hypertension-induced reduction in OT receptor mRNA expression, not altered by training. In contrast, training increased OT mRNA expression in sedentary and hypertensive rats, which may facilitate traininginduced cardiac performance. Key Words: hypothalamus Ⅲ exercise Ⅲ rats, spontaneously hypertensive Ⅲ neurotransmitter Ⅲ genetics Ⅲ autonomic nervous system Ⅲ immunohistochemistry H ypertension is a highly prevalent disease and a common risk factor for different cardiovascular diseases, with a major impact on morbidity and mortality. 1 Hypertensive individuals present with a series of functional and anatomic deficits, such as increased vascular resistance, vessel rarefaction, increased heart energy expenditure, increased stroke work, impaired baroreceptor reflex control, hormonal imbalance with overactivation of the renin-angiotensin system, and increased insulin resistance. Most of these effects contribute to increased sympathetic activity and depressed cardiovascular control. 1 On the other hand, exercise training has been associated with a variety of beneficial cardiovascular adjustments in hypertensive individuals, such as eutrophic remodeling of arterioles causing wall-lumen ratio normalization, 2,3 capillary angiogenesis and venule neoformation in exercised muscles resulting in increased vascular capacity and O 2 extraction, 3-7 and remodeling of the heart with simultaneous stroke volume increase and heart rate decrease. 8,9 Although there are ...