Thyroid hormone is a major regulator of thermogenesis, acting both in peripheral organs and on central autonomic pathways. Mice heterozygous for a point mutation in thyroid hormone receptor α1 display increased thermogenesis as a consequence of high sympathetic brown fat stimulation. Surprisingly, despite the hypermetabolism, their body temperature is not elevated. Here we show, using isolated tail arteries, that defective thyroid hormone receptor α1 signaling impairs acetylcholine-mediated vascular relaxation as well as phenylephrine-induced vasoconstriction. Using infrared thermography on conscious animals, we demonstrate that these defects severely interfere with appropriate peripheral heat conservation and dissipation, which in turn leads to compensatory alterations in brown fat activity. Consequently, when the vasoconstrictive defect in mice heterozygous for a point mutation in thyroid hormone receptor α1 was reversed with the selective α1-adrenergic agonist midodrine, the inappropriate heat loss over their tail surface was reduced, normalizing brown fat activity and energy expenditure. Our analyses demonstrate that thyroid hormone plays a key role in vascular heat conservation and dissipation processes, adding a unique aspect to its well-documented functions in thermoregulation. The data thus facilitate understanding of temperature hypersensitivity in patients with thyroid disorders. Moreover, the previously unrecognized connection between cardiovascular regulation and metabolic activity revealed in this study challenges the interpretation of several experimental paradigms and questions some of the currently derived hypotheses on the role of thyroid hormone in thermogenesis.adipose tissue | tail temperature T hyroid hormone affects energy metabolism, body temperature, and cardiovascular function (1, 2). This is evident in hypo-and hyperthyroid patients, who display metabolic and cardiovascular problems as well as inadequacies in heat and cold tolerance (3, 4). The latter effects are thought to be a consequence of a shift in obligatory thermogenesis, because thyroid hormone affects basal metabolic rate through the regulation of genes controlling cellular metabolism and mitochondrial function. In addition, facultative thermogenesis, brought about by shivering and brown adipose tissue (BAT) activation (5, 6), is also modulated by thyroid hormone. The recent discovery of BAT in adult humans, where previously thought to exist only in rodents and neonates (7), suggests that the role of BAT in thermoregulation and energy expenditure may be underestimated. Recently, a new role of thyroid hormone in facultative thermogenesis has emerged, controlling BAT via the central nervous system (8, 9). The importance of central thyroid hormone receptor α1 (TRα1) signaling for BAT activity was further supported by findings in mice heterozygous for a R384C mutation in TRα1 (TRα1+m), which display a strong hypermetabolism as the result of a central overactivation of BAT (10). However, the finding was unexpected, as the specific ...

Monocyte-endothelial cell adhesion is a key early event in atherogenesis. C-reactive protein (CRP), a cardiovascular risk marker, is known to stimulate ICAM and VCAM in human aortic endothelial cells (HAEC) and induces monocyte-endothelial cell adhesion. In this study, we examined the mechanisms by which native CRP promotes monocyte-endothelial cell adhesion under static conditions and tested the effect of CRP on adhesion under shear flow. Incubation of HAEC with CRP (Ͼ25 g/ml) upregulated NF-B activity, and this resulted in a significant increase in ICAM (54% increase, P Ͻ 0.001), VCAM (41% increase, P Ͻ 0.01), and monocyte-endothelial cell adhesion (44% increase, P Ͻ 0.02) compared with those of control. Preincubation with antibodies to CD32 and CD64 but not CD16 effectively inhibited this activation. Blocking NF-B activity with inhibitors or a dominant negative inhibitory B significantly decreased ICAM, VCAM upregulation, and subsequent monocyte-endothelial cell adhesion. Preincubation with antibodies to CD32 and CD64 or transient transfection with small interference RNA to CD32 attenuated CRPinduced NF-B activity, ICAM, VCAM, and monocyte-endothelial cell adhesion under static conditions. Also, the Syk kinase inhibitor piceatannol and MG-132, a proteasome degradation inhibitor, produced similar attenuation in NF-B activity, ICAM, VCAM, and adhesion. Furthermore, CRP-activated endothelial cells supported monocyte rolling, arrest, and transmigration in shear flow (2 dyn/ cm 2 ), and this was also inhibited by preincubation with antibodies to CD32 and CD64. Thus, in HAEC, CRP upregulates monocyteendothelial adhesion by activation of NF-B through engaging the Fc␥ receptors CD32 and CD64. C-reactive protein; human aortic endothelial cells; tissue-type plasminogen activator; plasminogen activator inhibitor INFLAMMATION IS PIVOTAL in all stages of atherosclerosis (15). Numerous prospective studies have shown that high levels of C-reactive protein (CRP) predict cardiovascular events, and several recent studies (11,20,28) have documented a proatherogenic, prothrombotic role for CRP. In endothelial cells, CRP has been shown to decrease endothelial nitric oxide synthase (eNOS), prostacyclin, and tissue-type plasminogen activator (tPA) and to upregulate plasminogen activator inhibitor-1 (PAI-1) and IL-8 (11). Monocyte-endothelial cell adhesion is a key early event in atherogenesis (16,19). After endothelial cell dysfunction, mononuclear cells, such as monocytes and T lymphocytes, transition from rolling to firm arrest and then diapedese into the subendothelial space. The rolling and tethering of leukocytes on the endothelium are orchestrated by adhesion molecules, such as selectins (E-selectin and Pselectin), cell adhesion molecules (ICAM-1 and VCAM-1), and integrins (1, 2). It has previously been shown that CRP induces the expression of ICAM and VCAM in human aortic endothelial cells (HAEC) and stimulates monocyte-endothelial cell adhesion under static conditions (18,25,26). In a recent study, Kawanami et al. (12) hav...

Key pointsr The role of the small G-protein Rac1 was investigated in smooth muscle, using a smooth muscle-specific knockout mouse and pharmacological blockers. r The results demonstrate a novel Rac1-associated signalling pathway for regulation of smooth muscle contraction. AbstractThe role of the small GTP-binding protein Rac1 in smooth muscle contraction was examined using small molecule inhibitors (EHT1864, NSC23766) and a novel smooth muscle-specific, conditional, Rac1 knockout mouse strain. EHT1864, which affects nucleotide binding and inhibits Rac1 activity, concentration-dependently inhibited the contractile responses induced by several different modes of activation (high-K + , phenylephrine, carbachol and protein kinase C activation by phorbol-12,13-dibutyrate) in several different visceral (urinary bladder, ileum) and vascular (mesenteric artery, saphenous artery, aorta) smooth muscle tissues. This contractile inhibition was associated with inhibition of the Ca 2+ transient. Knockout of Rac1 (with a 50% loss of Rac1 protein) lowered active stress in the urinary bladder and the saphenous artery consistent with a role of Rac1 in facilitating smooth muscle contraction. NSC23766, which blocks interaction between Rac1 and some guanine nucleotide exchange factors, specifically inhibited the α 1 receptor responses (phenylephrine) in vascular tissues and potentiated prostaglandin F2α and thromboxane (U46619) receptor responses. The latter potentiating effect occurred at lowered intracellular [Ca 2+ ]. These results show that Rac1 activity is required for active contraction in smooth muscle, probably via enabling an adequate Ca 2+ transient. At the same time, specific agonists recruit Rac1 signalling via upstream modulators, resulting in either a potentiation of contraction via Ca 2+ mobilization (α 1 receptor stimulation) or an attenuated contraction via inhibition of Ca 2+ sensitization (prostaglandin and thromboxane receptors).

Thyroid hormone has profound direct effects on cardiac function, but the hormonal interactions with the autonomic control of heart rate are unclear. Because thyroid hormone receptor (TR)-alpha1 has been implicated in the autonomic control of brown adipose energy metabolism, it might also play an important role in the central autonomic control of heart rate. Thus, we aimed to analyze the role of TRalpha1 signaling in the autonomic control of heart rate using an implantable radio telemetry system. We identified that mice expressing the mutant TRalpha1R384C (TRalpha1+m mice) displayed a mild bradycardia, which becomes more pronounced during night activity or on stress and is accompanied by a reduced expression of nucleotide-gated potassium channel 2 mRNA in the heart. Pharmacological blockage with scopolamine and the beta-adrenergic receptor antagonist timolol revealed that the autonomic control of cardiac activity was similar to that in wild-type mice at room temperature. However, at thermoneutrality, in which the regulation of heart rate switches from sympathetic to parasympathetic in wild-type mice, TRalpha1+m mice maintained sympathetic stimulation and failed to activate parasympathetic signaling. Our findings demonstrate a novel role for TRalpha1 in the adaptation of cardiac activity by the autonomic nervous system and suggest that human patients with a similar mutation in TRalpha1 might exhibit a deficit in cardiac adaptation to stress or physical activity and an increased sensitivity to beta-blockers.

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