Thyroid hormone and atherosclerosis

Thyroid hormone and atherosclerosis

Thyroid Hormone & Cardiovascular Vascular Pharmacology 52 (2010) 151–156 Contents lists available at ScienceDirect Vascular Pharmacology j o u r n ...

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Thyroid Hormone & Cardiovascular

Vascular Pharmacology 52 (2010) 151–156

Contents lists available at ScienceDirect

Vascular Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / v p h

Review

Thyroid hormone and atherosclerosis Toshihiro Ichiki ⁎ Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Japan Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences, Japan

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Article history: Received 23 September 2009 Accepted 30 September 2009 Keywords: Thyroid hormone Atherogenesis Coronary risk factors Renin–angiotensin system

a b s t r a c t It is generally accepted that the euthyroid state is preferred for the cardiovascular system because both hyperthyroidism and hypothyroidism cause or accelerate cardiovascular diseases. And hypothyroidism is known to be associated with atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension and impaired endothelial function. In addition, recent studies suggest that hypothyroidism is associated with the emerging risk factors for atherosclerosis such as hyperhomocysteinemia and an increase in C-reactive protein level. Thyroid hormone also has direct anti-atherosclerotic effects such as blood vessel dilatation, production of vasodilatory molecules, and inhibition of angiotensin II receptor expression and its signal transduction. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modifying risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in atherogenesis and a possible application of thyroid hormone mimetics for the therapy of hypercholesterolemia and atherosclerosis. © 2009 Elsevier Inc. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Hypothyroidism and atherosclerotic risk factors . . . . . . . . 2.1. Lipid profile . . . . . . . . . . . . . . . . . . . . . 2.2. Blood pressure . . . . . . . . . . . . . . . . . . . . 2.3. Endothelial function . . . . . . . . . . . . . . . . . . 2.4. Homocysteine, CRP and plasminogen activator inhibitor-1 3. Direct effects of thyroid hormone on the vasculature . . . . . 4. Thyroid hormone and angiogenesis . . . . . . . . . . . . . . 5. Thyroid hormone and the renin–angiotensin system . . . . . . 6. Thyroid hormone analogs . . . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Thyroid hormone has various effects on the cardiovascular system and both hyperthyroidism and hypothyroidism cause or accelerate cardiovascular diseases. Hyperthyroidism causes a hyperdynamic

⁎ Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan. Tel.: +81 92 642 5358; fax: +81 92 642 5374. E-mail address: [email protected] 1537-1891/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2009.09.004

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cardiovascular state including a faster heart rate, increased left ventricular contraction and relaxation, and atrial fibrillation. Hypothyroidism causes opposite cardiovascular changes, and is associated with the increased risk for atherosclerosis and ischemic heart disease. Epidemiological studies have suggested that patients with hypothyroidism have accelerated coronary atherosclerosis (Cappola and Ladenson, 2003). The Rotterdam study showed a higher prevalence of myocardial infarction in women with subclinical hypothyroidism compared with euthyroid women (Hak et al., 2000). It has been suggested that hypercholesterolemia, hypertension and impaired endothelial function in hypothyroid state enhance atherogenesis.

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Some emerging risk factors for atherosclerosis such as hyperhomocysteinemia and an increased C-reactive protein (CRP) level have also been shown to associate with overt as well as subclinical hypothyroidism (Cappola and Ladenson, 2003). Recent studies have shown that thyroid hormone also has direct effects on the blood vessel, which may attenuate atherogenesis. Although these studies suggest an anti-atherosclerotic effect of thyroid hormone and an association of hypothyroidism with atherogenesis, some recent clinical trials failed to show an association between thyroid function and cardiovascular events, indicating that the relationship between thyroid hormone and atherogenesis is still elusive and that further study is needed to establish the role of thyroid hormone in atherosclerotic cardiovascular diseases.

2. Hypothyroidism and atherosclerotic risk factors The recent National Health and Nutrition Examination Survey (NHANES III) study showed that the prevalence of subclinical and overt hypothyroidism was 0.3 and 4.3% in the United States, respectively (Hollowell et al., 2002). Observational studies generally support the idea that hypothyroidism accelerates coronary atherosclerosis. Autopsy studies of patients with overt hypothyroidism revealed accelerated atherosclerosis in the coronary arteries of these patients compared with age-matched controls (Vanhaelst et al., 1967) (Steinberg, 1968). Severe coronary atherosclerosis was observed in 84% (n = 25) of myxedema patients whereas 46% of age-matched control cases (n = 50) had severe coronary atherosclerosis (Vanhaelst et al., 1967). A recent report also confirmed higher prevalence of coronary heart disease in patients with subclinical hypothyroidism (56% in patients with subclinical hypothyroidism vs. 16% in euthyroid older persons) (Mya and Aronow, 2002). The Rotterdam study provided the most striking data on the greater cardiovascular risk in patients with subclinical hypothyroidism. This study showed that elderly women with subclinical hypothyroidism had a higher prevalence of myocardial infarction (odds ratio, 2.3 [95% CI, 1.3 to 4.0]) independently of blood pressure or high-density lipoprotein (HDL) cholesterol levels (Hak et al., 2000). However, another study showed no differences in the prevalence of angina or myocardial infarction between euthyroid individuals and patients with subclinical hypothyroidism (hazard ratios 1.07, 95% CI, 0.90–1.28) (Cappola et al., 2006). Rodondi et al. (2005) followed 2730 persons aged 70 to 79 years with subclinical hypothyroidism and found that subclinical hypothyroidism was associated with an increased risk of heart failure but not with the risk of coronary heart disease or peripheral arterial disease. Although controversy still exists, a meta-analysis showed that subclinical hypothyroidism is significantly associated with coronary heart disease at baseline (RR: 1.533) and death from cardiovascular causes at follow-up (RR: 1.278) (Singh et al., 2008). Ochs et al. also showed that subclinical hypothyroidism is associated with a modest increase in the risk of coronary heart diseases (Ochs et al., 2008) by a meta-analysis. However, it remains to be determined whether thyroxine replacement therapy reduces the risk of coronary heart disease in these patients. A study on the progression of coronary atherosclerosis in patients undergoing coronary angiography showed that treatment of hypothyroidism affected atherogenesis, although the number of patients enrolled was very small (Perk and O'Neill, 1997). All patients with inappropriate treatment (n =5) for hypothyroidism showed angiographic progression of coronary atherosclerosis whereas only 2 of 7 patients who were treated adequately with replacement therapy showed progression. Intima-media thickness (IMT) of the carotid artery measured by ultrasonography represents early atherosclerotic changes and is generally accepted as a surrogate marker of future cardiovascular events (O'Leary and Polak, 2002). Nagasaki et al. showed that IMT in patients with overt hypothyroidism was significantly higher compared with that in euthyroid control subject (0.635 ± 0.08 mm vs. 0.559 ± 0.021 mm in control, P < 0.005) (Nagasaki et al., 2003). 1-year

treatment with levothyroxine reversed the increased IMT in hypothyroid patients (0.552 ± 0.015 mm). A large scale randomized trial to examine the benefit of thyroid hormone replacement therapy in patients with both coronary artery disease and subclinical as well as overt hypothyroidism is warranted.

2.1. Lipid profile Hypothyroidism has been shown to associate with several traditional risk factors for atherosclerosis. Overt hypothyroidism is characterized by hypercholesterolemia (Morris et al., 2001). And 4– 14% of hypercholesterolemic patients were reported to be in the hypothyroid state (Diekman et al., 1995). An elevation of total cholesterol (9.4 ± 1.0 vs. 6.4 ± 0.1 mmol/L in control, P < 0.001), lowdensity lipoprotein (LDL) cholesterol (6.3 ± 0.8 vs. 3.7 ± 0.1 mmol/L in control, P < 0.001), and apolipoprotein B level (101.4 ± 12.4 vs. 75.2 ± 2.2 mg/dL in control, P < 0.025) was reported in patients with overt hypothyroidism (Staub et al., 1992). An experimental study demonstrated that LDL receptor mRNA expression was decreased in the hypothyroid rats by 50%, resulting in a prolongation of half-life of LDL cholesterol, which may be a possible mechanism for the increased LDL level in the hypothyroid state (Staels et al., 1990). Furthermore, LDL is more susceptible to oxidation, a modification that increases its atherogenicity, in patients with hypothyroidism (Sundaram et al., 1997). In addition to LDL, HDL cholesterol whose concentration is inversely related to atherosclerosis, was decreased in the hypothyroid state (1.15 ± 0.40 vs. 1.34 ± 0.40 mmol/L in control, P < 0.05) (Kung et al., 1995). Therefore, the lipid profile in patients with overt hypothyroidism is generally prone to enhancement of atherosclerosis. The effect of subclinical hypothyroidism on the lipid profile is controversial. A meta-analysis on the effect of thyroid hormone replacement on the lipid profile revealed a modest reduction of LDL cholesterol level (10 mg/dL) and no change in the HDL cholesterol level in patients with subclinical hypothyroidism (Danese et al., 2000).

2.2. Blood pressure Thyroid hormone is an important regulator of blood pressure level. It was reported that diastolic hypertension (84.6 ± 7.9 mm Hg vs. 76.4 ± 6.8 mm Hg in baseline, P < 0.05) was developed after thyroidectomy in patients with normal blood pressure (Fommei and Iervasi, 2002), indicating an acute effect of thyroid hormone on diastolic blood pressure. The prevalence of hypertension was 3 times higher in patients with overt hypothyroidism compared with the euthyroid group (14.8% vs. 5.5% in control) (Saito and Saruta, 1994). In another study, 3.6% of hypertensive patients were identified as hypothyroid (Bing et al., 1980). Adequate thyroid hormone replacement successfully reduced diastolic blood pressure in these patients. Systolic blood pressure is also increased in hypothyroidism. Increases in peripheral vascular resistance (Graettinger et al., 1958) and arterial stiffness (Obuobie et al., 2002) are suggested as potential mechanisms for the development of systolic and diastolic high blood pressures in hypothyroid patients, respectively. Brachial-ankle pulse wave velocity is a parameter of arterial stiffening. Nagasaki et al. (2006) showed that diastolic blood pressure (78.3 ± 2.3 mm Hg vs. 67.3 ± 2.3 mm Hg in a normal subject, P < 0.005) and brachial-ankle pulse wave velocity (1864.7 ± 78.4 cm/s vs. 1381.2 ± 47.5 cm/s in normal subject, P < 0.0001) were increased in patients with subclinical hypothyroidism. Because the brachial-ankle pulse wave velocity was significantly associated with the systolic and diastolic blood pressure levels but not with free thyroxine or levothyroxine levels, the authors suggested that increased diastolic blood pressure level may be due to the increased arterial stiffness in patients with hypothyroidism.

2.3. Endothelial function Endothelial dysfunction is generally accepted as an early step of the atherosclerosis. It was reported that endothelial dysfunction was present in the hypothyroid state by measurement of flow-mediated endothelium-dependent vasodilatation (Lekakis et al., 1997), which indicates an association between hypothyroidism and atherosclerosis. A reduction of NO availability is suggested as the mechanism of endothelial dysfunction in patients with hypothyroidism (Taddei et al., 2003). It has been proved that replacement of thyroid hormone improved endothelial function in patients with hypothyroidism (Taddei et al., 2003; Papaioannou et al., 2004). However, it is difficult to determine whether the endothelial dysfunction is due to a direct effect of thyroid hormone deficiency or indirect effects of hypercholesterolemia and high blood pressure in hypothyroid patients, which are well known to cause endothelial dysfunction (Giannotti and Landmesser, 2007). 2.4. Homocysteine, CRP and plasminogen activator inhibitor-1 Hyperhomocysteinemia, an elevation of C-reactive protein (CRP) level, and an increase in plasminogen activator inhibitor-1 (PAI-1) level are emerging new risk factors for atherosclerotic cardiovascular diseases. Although it has been reported that the serum levels of these factors were increased in patients with hypothyroidism, the mechanisms by which thyroid hormone regulates these factors have not been established. Hyperhomocysteinemia is an independent risk factor for premature atherosclerosis (Welch and Loscalzo, 1998). Homocysteine is believed to accelerate atherosclerosis through an increase in oxidative stress, impairment of endothelial function and induction of thrombosis (Guthikonda and Haynes, 2006). Several studies have shown an elevation of serum homocysteine level in patients with overt hypothyroidism (12.4 vs. 8.8 mmol/L in the non-hypothyroid group, P < 0.05) (Morris et al., 2001; Christ-Crain et al., 2003; Sengul et al., 2004). The serum homocysteine level was successfully reduced after supplementation of thyroid hormone (Christ-Crain et al., 2003). A mild decrease in the serum homocysteine level in patients with overt hyperthyroidism was also reported. However, several studies showed that subclinical hypothyroidism does not affect serum homocysteine level (Graettinger et al., 1958; Christ-Crain et al., 2003; Hueston et al., 2005). Several factors such as genetic, nutritional (vitamin B6, B12 and folate) and acquired factors (renal function, smoking) are reported to affect serum homocysteine level. Thyroid hormone modulates expression of genes involved in the metabolism of homocysteine (Nair et al., 1994), resulting in the change in the serum homocysteine level (Ford et al., 1989). It is, however, suggested, that changes in folate level (Lien et al., 2000) or renal function (Barbe et al., 2001) may be responsible for the increased serum homocysteine level in patients with hypothyroidism. CRP is an acute phase-reactant protein that is increased in response to acute and chronic inflammation. An increase in serum CRP level is significantly associated with future cardiovascular events (Ridker, 2007). The ability of high sensitivity (hs)-CRP to predict cardiovascular risk has been demonstrated in a broad range of patients with cardiovascular diseases such as stable angina, undergoing elective angioplasty as well as coronary artery bypass graft (Tsimikas et al., 2006). hs-CRP is also useful in the setting of primary prevention of cardiovascular events. CRP is not only a biomarker of atherosclerosis but also an active mediator that enhances vascular lesion formation (Paul et al., 2004). An increase in serum CRP level in patients with overt and subclinical hypothyroidism was reported (2.8 ± 2.4 vs. 1.8 ± 1.9 mg/ L in the non-hypothyroid group, P < 0.05) (Christ-Crain et al., 2003). However, replacement of thyroid hormone in patients with subclinical hypothyroidism did not change CRP level (Luboshitzky and Herer,

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2004). Another study even failed to detect any increase in CRP level in patients with subclinical hypothyroidism (Toruner et al., 2008). The molecular mechanism for the thyroid hormone regulation of CRP level is not clear. However, the secondary effects of increased blood pressure and changes in the lipid profile may be involved. A decrease in the fibrinolytic activity including lower D-dimer levels and higher levels of PAI-1 was observed in hypothyroid women (Canturk et al., 2003; Chadarevian et al., 2001). Therefore, it is assumed that patients with hypothyroidism have a greater risk for thrombosis. However, studies failing to show any effects of hypothyroidism on PAI-1 level were also reported (Erem, 2006). Atherogenic risk factors associated with hypothyroidism are listed in Table 1. 3. Direct effects of thyroid hormone on the vasculature The studies described above have suggested that hypothyroidism modifies risk factors for atherosclerosis and indirectly affects atherogenesis. In addition, recent studies have shown that thyroid hormone has direct effects on the vasculature. It is well known that thyroid hormone reduces systemic vascular resistance. Ojamaa et al. reported that thyroid hormone induced relaxation of vascular smooth muscle cells (VSMCs) through a direct effect (Ojamaa et al., 1996). The specific binding sites for triiodothyronine (T3) were identified in the plasma membrane of VSMCs. Relaxation occurred within 10 min. Therefore, T3-induced relaxation is suggested to be a non-genomic effect on VSMC. In endothelial cells, the authors failed to detect an increase in cGMP level after T3 stimulation, suggesting that T3 did not induce nitric oxide (NO) production. However, a recent study suggested that endothelial NO plays a critical role in thyroid hormone-induced vasodilatation (Napoli et al., 2001). NO inhibition by NG-monomethyl-L-arginine (L-NMMA) markedly decreased forearm blood flow in patients with hyperthyroidism compared with normal subjects or euthyroid patients after methimazole treatment. L-NMMA decreased forearm blood flow by 2.8 ± 0.6 fold and 0.61 ± 0.7 fold in patients with hyperthyroidism and normal subjects, respectively (P < 0.05). A subsequent study also reported that endothelium-dependent vasodilatation was impaired even in patients with subclinical hypothyroidism (Taddei et al., 2003), suggesting an important role of NO in T3induced vasodilatation. In accordance with the results of these in vivo studies, Hiroi et al. (2006) showed that thyroid hormone activated endothelial NO synthase through phosphatidylinositol 3-kinase/Akt pathway. The reason for the apparent difference in the results between Ojamaa et al. (1996) and Hiroi et al. (2006) is not clear. A seminal study by Mizuma et al. (2001) showed that VSMCs expressed type II iodothyronine deiodinase, which converts inactive precursor thyroxine (T4) to T3, an active thyroid hormone. The type II iodothyronine deiodinase activity is increased in the hypothyroid state and believed to play an important role in the maintenance of intracellular T3 level. It was also shown in this study that VSMCs expressed mRNA of 4 thyroid hormone receptors (TR) designated as α1, α2, β1 and β2. These results suggest that VSMCs are physiological targets of the thyroid hormone and that T3 modulates gene expression through a classical genomic effect in addition to the nongenomic effect on the vascular tone.

Table 1 Atherogenic risk factors associated with hypothyroidism. Low-density lipoprotein cholesterol Blood pressure C-reactive protein Homocysteine Plasminogen activator inhibitor-1 D-dimer

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Although several target genes of T3 have been identified in cardiac myocytes (Klein and Ojamaa, 2001), relatively little is known about the target genes of T3 in VSMC. A recent report showed that T3 at physiological concentrations increased matrix Gla protein in VSMCs by 3–8 fold (Sato et al., 2005). Because matrix Gla protein is known to act as a potent inhibitor of vascular calcification (Zebboudj et al., 2003), it is suggested that thyroid hormone may prevent vascular calcification that is involved in the progression of atherosclerotic plaque. Adrenomedullin is a potent vasorelaxant and antioxidant peptide. It was reported that T3 induced adrenomedullin expression in rat endothelial cells (Isumi et al., 1998). The induction of adrenomedullin may be one of the mechanisms of the reduction in the vascular tone by T3. Adrenomedullin expression was also induced in VSMC by T3 (Imai et al., 1995). A role of T3 in the metabolism of extracellular nucleotide was recently reported (Tamajusuku et al., 2006). T3 did not affect ATP or ADP hydrolysis, but increased AMP hydrolysis in VSMC, suggesting that T3 increases production of adenosine that is an important local vasodilator molecule. The increase in AMP hydrolysis is due to an increase in the expression level of ecto-5′-nucleotidase (ecto-5′-NT) that transforms AMP to adenosine. Induction of ecto-5′-NT may be another possible mechanism for T3-induced vascular relaxation. Cyclic ADP-ribose (ADPR) is a novel nucleotide that induces Ca2+ release from ryanodine sensitive channels. de Toledo et al. (1997) showed that thyroid hormone activated ADPR cyclase activity that converts β-NAD+ to cyclic ADPR in rat VSMC. The increase in cADPR may induce the contraction of VSMC due to Ca2+ release. However, functional role of cADPR in VSMC is not fully elucidated. It was previously reported that T3, at a relatively high concentration, downregulated angiotensin II type 1 receptor (AT1R) expression in VSMCs (47% reduction at 1 μM of T3, P < 0.05) (Fukuyama et al., 2003). Downregulation of aortic AT1R expression was observed in hyperthyroid rats induced by an intraperitoneal administration of T3. The downregulation of AT1R may also be involved in the sustained vasodilatation in the hyperthyroid state. In addition, Fukuyama et al. (2006) recently showed that T3 inhibited AT1R signaling activated by angiotensin II. T3 inhibited angiotensin II-induced activation of cAMP response element binding protein (CREB), a 43 kDa nuclear transcription factor involved in a wide range of gene expression, and thereby proliferation of VSMC. Although a previous study suggested that angiotensin II-induced CREB activation was dependent on the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (Funakoshi et al., 2002), T3 did not affect the activity of these kinases. Instead, it was shown that CREB interacted directly with TR. Although the precise mechanism for the inhibition of CREB activity by TR is not clarified, structural changes induced by binding of T3 to TR was supposed to interfere with the phosphorylation of CREB. Neointimal formation after balloon injury of rat carotid artery was attenuated in the hyperthyroid rats with decreased phosphorylation of CREB in the neointima. Although BrdU incorporation was decreased in the neointima of the hyperthyroid rats, the number of TUNEL positive cells was not changed, suggesting that T3 mainly inhibits proliferation of VSMC in vivo without a significant effect on apoptosis. Recently, Kasahara et al. (2006) reported that T3 as well as T4 inhibited platelet-derived growth factor-induced DNA synthesis of VSMC, which seems to be consistent with the results of the study by Mizuma et al. (2001) that showed the presence of type II deiodinase in VSMC. These studies suggest that T3 inhibits VSMC growth and blunts the effect of angiotensin II through AT1R, which may be a novel antiatherosclerotic mechanism of thyroid hormone. A recent study examined the role of thyroid hormone in the prognosis of patients with heart disease. In this study, it was reported that low-T3 state is a strong predictor of death in patients with cardiac diseases (Iervasi et al., 2003). The logistic multivariate analysis revealed that free T3 was the highest independent predictor of

death (hazard ratio 0.395, P = 0.003) in patients with heart diseases. Low serum concentrations of T3 in patients with heart diseases may be an adaptive mechanism to preserve energy. However, low T3 shows negative impact on the prognosis of patients with heart diseases, which may be due to an adverse effect of low-T3 state on blood vessels. Several target genes of T3 in the blood vessel is summarized in Table 2. 4. Thyroid hormone and angiogenesis It is reported that thyroid hormone enhances angiogenesis. T3 induced coronary angiogenesis as well as cardiac hypertrophy. The T3-induced angiogenesis took place at the capillary level and was dependent on the upregulation of basic fibroblast growth factor, a potent angiogenic growth factor (Tomanek et al., 1998). A subsequent study (Davis et al., 2004) showed that thyroid hormone-induced angiogenesis was inhibited by PD98059, an ERK kinase inhibitor. In this study, it was shown that T4 was also capable of inducing angiogenesis, although the potency of T4 was much weaker than that of T3. Bergh et al. (2005) showed that the angiogenic effect of T3 was mediated by αVβ3 integrin that worked as a receptor for T3, suggesting that T3-induced angiogenesis is independent of TR. An imbalance between angiogenesis and cardiac hypertrophy is one of the causes that induce heart failure in a pressure-overloaded heart. Makino et al. reported that T3 restored the capillary density of the pressure-overloaded heart (Makino et al., 2009). The authors suggested that a decrease in the TR-β in endothelium is responsible for coronary artery rarefaction in pathologically hypertrophied heart. Angiogenesis may be a double-edged sword for the cardiovascular system (Ribatti et al., 2008). For ischemic myocardium or ischemic limb, formation of collateral arteries is beneficial. However, neovascularization in the atherosclerotic plaque is believed to destabilize the plaque and may predispose plaque rupture and subsequent thrombosis, a main mechanism of acute coronary syndrome (Jain et al., 2007). It has not been determined whether thyroid hormone-induced angiogenesis is beneficial or detrimental for the stability of atherosclerotic plaque. 5. Thyroid hormone and the renin–angiotensin system The renin–angiotensin system plays an important role in the acceleration of atherogenesis. T3 was reported to increase production and secretion of renin (Resnick and Laragh, 1982). More than half of hypothyroid patients showed low plasma renin activity (Saruta et al., 1980). Therefore, plasma renin activity is increased in the hyperthyroid state whereas it is decreased in the hypothyroidism. T3 increases production of angiotensinogen from liver in rats (Marchant et al., 1993). However, another report showed no change in the level of angiotensinogen in the hyperthyroid dog (Sernia et al., 1993). It is not clear whether different results are due to different species used. Interestingly, both studies reported an increase in plasma angiotensin II level (Marchant et al., 1993; Sernia et al., 1993), suggesting that the systemic renin–angiotensin system is activated in hyperthyroidism. Hyperthyroidism increased angiotensin type 2 receptor (AT2R) expression in the heart whereas AT1R expression was decreased

Table 2 Target genes of thyroid hormone in blood vessel. Adrenomedullin Matrix Gla protein Angiotensin II type 1 receptor Ecto-5′-nucleotidase ADP-ribose cyclase Basic fibroblast growth factor

(Marchant et al., 1993). Because angiotensin II downregulates AT1R expression (Ichiki et al., 2001), the increased angiotensin II may be responsible for the decreased AT1R level in the heart. However, as described above, T3 decreases AT1R expression in VSMC through a direct effect (Fukuyama et al., 2003). Therefore, the cardiac AT1R may be also decreased through a direct effect of T3 on the cardiac myocytes. The overall effect of thyroid hormone on the renin– angiotensin system (an increased angiotensin II level and downregulation of AT1R expression) seems to favor stimulation of AT2R, which is generally believed to oppose AT1R function and be protective against cardiovascular disease (Matsubara, 1998). An opposite situation may be observed in the hypothyroid state and accelerate atherogenesis.

6. Thyroid hormone analogs The prevalence of obesity is pandemic and metabolic abnormalities associated with obesity such as hyperlipidemia, insulin resistance and high blood pressure accelerate atherosclerotic cardiovascular diseases. Given the metabolic changes in obesity, thyroid hormone seems to have a potential therapeutic implication, such as cholesterol lowering effect, improvement of energy expenditure and blood vessel dilation. However, clinical application of thyroid hormone is hampered probably because of its positive chronotropic effect on the heart. The Coronary Drug Project examined the effect of dextrothyroxine on the survival of patients who suffered one heart attack (Ahd, 1972). Dextrothyroxine is a D-enantiomer of thyroxine that is an Lconformation. Although serum cholesterol levels were decreased, the mortality was increased by dextrothyroxine. This study and several other failed clinical trials of a thyroid hormone analog discouraged investigators from using thyroid hormone analogs for the treatment of ischemic heart disease. However, recent development of thyroid hormone analogs that are able to uncouple the beneficial effects from unfavorable effects of thyroid hormone is encouraging (Baxter and Webb, 2009). Because thyroid hormone receptor isoforms differentially couple to transcription of target genes and mediate different physiological functions, these thyroid hormone mimetics selectively activate or antagonize these isoforms. GC-1, one of the TR-β selective agonists, is reported to reduce serum cholesterol level without an increase in heart rate (Trost et al., 2000), which may be suitable for the treatment of hypercholesterolemia in patients with ischemic heart disease. Several thyroid hormone mimetics are under development for clinical use (Baxter and Webb, 2009).

7. Conclusion Thyroid hormone has anti-atherosclerotic effects and hypothyroidism accelerates atherogenesis through modification of atherosclerotic risk factors and direct effects on the blood vessel. It is recommended to treat overt hypothyroidism cautiously in patients with cardiovascular diseases whereas it remains to be determined whether treatment of subclinical hypothyroidism with thyroid hormone replacement reduces the risk of cardiovascular events. However, accumulating evidence from basic studies suggests that maintaining the euthyroid state is beneficial to prevent the progression of atherosclerosis. Newly developed thyroid hormone mimetics are promising for the treatment of hypercholesterolemia and atherosclerotic cardiovascular diseases.

Acknowledgement This study was supported by Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (17590742).

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