Cardiovascular manifestations are a frequent finding in hyperthyroid and hypothyroid states. In this review, potential mechanisms by which thyroid hormones may exert their cardiovascular effects and pathophysiological consequences of such effects are briefly discussed. Two major concepts have emerged about how thyroid hormones exert their cardiovascular effects. First, there is increasing evidence that thyroid hormones exert direct effects on the myocardium, which are mediated by stimulation of specific nuclear receptors, which in turn leads to specific mRNAs production. Furthermore, there is some evidence that thyroid hormones may also activate extranuclear sites and may directly alter plasma membrane function. Second, thyroid hormones interact with the sympathetic nervous system by altering responsiveness to sympathetic stimulation presumably by modulating adrenergic receptor function and/or density. Pathophysiological consequences of such direct and indirect thyroid hormone effects include increased myocardial contractility and relaxation that may be related to stimulation by T3 of specific myocardial enzymes. However, when left ventricular hypertrophy occurs in association with hyperthyroidism, it may be related to either direct thyroid hormone-induced stimulation of myocardial protein synthesis or to thyrotoxicosis-induced increases in cardiac work load. Although hyperthyroidism generally has little or no effect on mean arterial blood pressure, hypothyroidism is often associated with increases in diastolic blood pressure that are reversible after hormone substitution and may be mediated in part by sympathetic activation. Moreover, there is increasing evidence that thyroid hormones have direct chronotropic effect on the heart that are independent of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

The three subtypes of the peroxisome proliferatoractivated receptors (PPAR␣, ␤/␦, and ␥) form heterodimers with the 9-cis-retinoic acid receptor (RXR) and bind to a common consensus response element, which consists of a direct repeat of two hexanucleotides spaced by one nucleotide (DR1). As a first step toward understanding the molecular mechanisms determining PPAR subtype specificity, we evaluated by electrophoretic mobility shift assays the binding properties of the three PPAR subtypes, in association with either RXR␣ or RXR␥, on 16 natural PPAR response elements (PPREs). The main results are as follows. (i) PPAR␥ in combination with either RXR␣ or RXR␥ binds more strongly than PPAR␣ or PPAR␤ to all natural PPREs tested. (ii) The binding of PPAR to strong elements is reinforced if the heterodimerization partner is RXR␥. In contrast, weak elements favor RXR␣ as heterodimerization partner. (iii) The ordering of the 16 natural PPREs from strong to weak elements does not depend on the core DR1 sequence, which has a relatively uniform degree of conservation, but correlates with the number of identities of the 5-flanking nucleotides with respect to a consensus element. This 5-flanking sequence is essential for PPAR␣ binding and thus contributes to subtype specificity. As a demonstration of this, the PPAR␥-specific element ARE6 PPRE is able to bind PPAR␣ only if its 5-flanking region is exchanged with that of the more promiscuous HMG PPRE.

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The peroxisome proliferator-activated receptors (PPARs) are a subgroup of nuclear receptors activated by fatty acids and eicosanoids. In addition, they are subject to phosphorylation by insulin, resulting in the activation of PPAR␣, while inhibiting PPAR␥ under certain conditions. However, it was hitherto unclear whether the stimulatory effect of insulin on PPAR␣ was direct and by which mechanism it occurs. We now demonstrate that amino acids 1-92 of hPPAR␣ contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPAR␣ revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. The characterization of a strong AF-1 region in PPAR␣, stimulating transcription one-fourth as strongly as the viral protein VP16, is compatible with the marked basal transcriptional activity of this isoform in transfection experiments. However, it is intriguing that the activity of this AF-1 region is modulated by the phosphorylation of two serine residues, both of which must be phosphorylated in order to activate transcription. This is in contrast to PPAR␥2, which was previously shown to be phosphorylated at a single site in a motif that is not homologous to the sites now described in PPAR␣. Although the molecular details involved in the phosphorylation-dependent enhancement of the transcriptional activity of PPAR␣ remain to be elucidated, we demonstrate that the effect of insulin on the AF-1 region of PPAR␣ can be mimicked by the addition of triiodothyronine receptor ␤1, a strong binder of corepressor proteins. In addition, a triiodothyronine receptor ␤1 mutant deficient in interacting with corepressors is unable to activate PPAR␣. These observations suggest that the AF-1 region of PPAR␣ is partially silenced by corepressor proteins, which might interact in a phosphorylation-dependent manner.

A B S T R A C T Diet-induced alterations in thyroid hormone concentrations have been found in studies of long-term (7 mo) overfeeding in man (the Vermont Study). In these studies ofweight gain in normal weight volunteers, increased calories were required to maintain weight after gain over and above that predicted from their increased size. This was associated with increased concentrations of triiodothyronine (T3

In 9 euthyroid obese volunteers, as previously reported, 4 weeks of total caloric deprivation resulted in a striking decrease in serum 3,5;3'-triiodothyronine (T3) concentration. The present studies reveal that this decrease in serum T3 is accompanied by a proportionately similar increase in the serum concentration of 3,3',5' -T3 (reverse T3; rT3). In four additional obese volunteers given suppressive doses of sodium-Lthyroxine (T4) for 1 month prior to fasting, serum T3 concentration declined sharply during a 6-11 day period of fast, while rT3 concentration increased strikingly. Concentrations of both T3 and rT3 returned to control values during a 5 day period of refeeding. The findings indicate that caloric deprivation results in an alteration in peripheral T4 metabolism away from generation of T3 and toward the generation of rT3. Since the former is more active than T4, and the latter is essentially inactive, caloric deprivation appears to shunt peripheral T4 metabolism from activating to inactivating pathways.

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