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Brief Reviews |
From the First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Japan
Correspondence to Johji Kato, MD, PhD, First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. E-mail jkjpn{at}med.miyazaki-u.ac.jp
| Abstract |
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The vasodilator peptide adrenomedullin exerts various vascular actions, and its gene is expressed in three layers of the vascular wall. Both pharmacological and gene-manipulation studies showed an inhibitory effect of adrenomedullin on intimal thickening and perivascular hyperplasia, suggesting a possible role in inhibiting the progression of vascular damage and remodeling.
Key Words: adrenomedullin vasodilatation endothelium smooth muscle cell arteriosclerosis
| Introduction |
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| Biochemistry of AM |
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In an effort to isolate unknown bioactive peptides having sequence homology with AM, another member belonging to the CGRP superfamily was recently discovered independently by two groups and named intermedin/AM-2.8,9 Human intermedin/AM-2 consists of 47 amino acid residues with an intramolecular ring structure formed by a disulfide bond and amidated tyrosine at the C terminus, showing structural homology with AM.8,9 Intermedin/AM-2 was shown to shear the receptors with AM by cultured cells,8 and in accord with this, it exerted vasodilator actions similar to AM ex vivo.10 However, data on the biochemical and pharmacological features of this novel peptide are currently very limited, and further characterization, such as the tissue distribution and effects on vascular cells, is necessary to discuss its role in blood vessels.
| Vasodilator Action of AM |
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AM has been shown to exert an endothelium-dependent vasodilatation via the NO-cyclic GMP (cGMP) pathway in rat aorta, in renal or hindquarter vascular bed of rats, and in canine kidneys.1417 In a further analysis of the mechanism, AM dilated rat aorta by activating phosphatidylinositol 3-kinase (PI3K) and Akt via the Ca2+/calmodulin-dependent pathway, which leads to increased production of NO through phosphorylation of endothelial NO synthase.18 On the other hand, endothelium-independent vasodilatation by AM has also been shown ex vivo in experiments with dog arteries or porcine coronary artery.19,20 The mechanisms so far proposed for endothelium-independent vasodilatation are an increase in the intracellular cyclic AMP (cAMP) level, a decrease in the Ca2+ concentration, and the activation of K+ channels in vascular smooth muscle cells (SMCs).2123
In humans, similarly to animals, intravenous infusion of AM lowered systemic and pulmonary vascular resistance, reducing blood pressure and increasing heart rate.24 AM-induced forearm arterial vasodilatation in healthy human subjects was attenuated by N-monomethyl-L-arginine (L-NMMA).25 In human coronary arterioles, vasodilatation induced by AM ex vivo was found to be dependent on the generation of NO and the activation of K+ channels, but not on guanylate or adenylate cyclase.26 A difference between species was also observed regarding the mechanisms. For example, pulmonary vasodilator responses were reduced by N-nitro-L-arginine methyl ester (L-NAME) in rats, but not in cats.27 Currently, there is little data available on the vasodilator effect on veins, whereas Barder et al reported that vasodilatation of femoral veins in canines was endothelium-dependent, but independent of cAMP and cGMP.28 Thus, the mechanism by which AM achieves direct vasodilatation appears to differ depending on species, the size of blood vessels, or regions where the vessels are isolated.
| Receptors Mediating Vascular Actions of AM |
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| AM Production in Blood Vessels and Atherosclerotic Lesions |
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Immunoreactivity for AM was reported to be detected in SMCs of the intima and media of human atherosclerotic lesions.40 Interestingly, its expression in coronary artery plaques obtained by directional atherectomy was augmented in patients with unstable angina in comparison with stable angina.45 This finding is consistent with cell culture studies showing that AM production and secretion from cultured vascular SMCs were increased by factors, presumably proatherogenic, such as angiotensin II, endothelin-1, aldosterone, interleukin-1ß (IL-1ß), and tumor necrosis factor-
(TNF-
).38,46,47 In addition, aldosterone was shown to stimulate AM production in cultured adventitial fibroblasts as well as in vascular SMCs.38,39 Macrophages play a pivotal role in the progression of atherosclerotic vascular lesions.1 Production of AM was detected in macrophages not only in a cell culture experiment,48 but also by immunohistochemical analysis where intense positive staining was found in advanced atherosclerotic vascular lesion of humans.40
| Circulating AM in the Bloodstream |
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To identify the organs or tissues contributing to the plasma AM level, we examined the plasma levels of AM of various sites in blood vessels of patients with ischemic heart disease.54 What we found was a step-up in plasma AM levels between the femoral artery and vein.54 Taking the active secretion of AM from cultured vascular cells into account, it seems likely that the vasculature contributes to the plasma AM level, secreting AM into the bloodstream. On the other hand, there was found to be a step-down between the plasma AM levels of the pulmonary artery and capillary.54 Substantial levels of AM gene expression were detected in the lungs and the presence of AM peptide in the pulmonary vasculature was immunohistochemically proven,35,55 but the lungs appear to be a target organ or a site for the clearance of circulating AM peptide rather than an AM-secreting organ. Consistent with this notion is the report of abundant expression of AM receptors in the lungs.56
| Plasma Level of AM in Arteriosclerosis |
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In the latter part of this review, vascular protective effects of AM will be discussed based on the results of cell culture and animal experiments. An important issue we need to mention in this section, therefore, is the significance of the increased plasma AM levels in patients with arteriosclerosis. Because of active production of AM in cultured vascular cells and vessel walls, AM has been assumed to act in a autocrine or paracrine fashion.3,4,3740 Indeed, blockade of the actions of endogenous AM with anti-AM antibody or the AM antagonists impaired the vascular protective effects in vitro.61,62 Meanwhile, according to our experiments in vivo,63,64 the long-term infusion of AM significantly suppressed neointimal formation and adventitial hyperplasia, raising plasma AM levels by 1 to 2 fmol/mL, an increase within the physiological range. This suggests a possible role for AM, not only as a local modulator, but also as a factor circulating in the blood.
| Vascular Protective Effects In Vitro |
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Furthermore, AM was shown to cause vascular regeneration by promoting the proliferation and migration of cultured vascular endothelial cells.67 AM promoted re-endothelialization of wounded human umbilical vein endothelial cells, and this effect was attenuated by inhibitors for protein kinase A and PI3K, suggesting an action mediated by cAMP and the PI3KAkt pathway.67 Stimulation of the proliferation and migration of endothelial cells may be involved in the angiogenic action of AM, which will be discussed later in this review. Although the mechanisms of action are still under investigation, these effects of AM on endothelial cells may be protective against vascular damage and arteriosclerosis.
The proliferation of vascular SMCs in the media and intima of arteries is involved in the progression of vascular remodeling or atherosclerotic lesions. Because AM is produced by SMCs in the media, its effects on the proliferation and migration of this type of cell were tested in vitro; however, there has been some inconsistency regarding the actions of AM. AM was shown to inhibit the proliferation of cultured SMCs via a mechanism mediated by cAMP,68 whereas Iwasaki et al found that AM stimulated proliferation of the cells in a mitogen-activated protein kinasedependent manner.69 Horio et al reported an inhibitory effect of AM on the migration of cultured SMCs, which is presumably mediated by intracellular cAMP.70 Inhibition of the migration of SMCs by AM was confirmed by an independent group,34 but according to this report, AM inhibited migration via a cAMP-independent mechanism.34 These discrepancies may have resulted from differences in the experimental conditions or types of cultured cells used, though there has currently been no clear explanation. Meanwhile, as discussed in the next section, recent studies in vivo suggest that AM inhibits intimal hyperplasia induced by periarterial cuff or by intimal balloon injury.
Another vascular protective action of AM recently reported in SMCs was a reduction in the generation of reactive oxygen species (ROS), a group of molecules involved in vascular damage and the progression of arteriosclerosis. The generation of intracellular ROS induced by angiotensin II was inhibited by AM, in a cAMP- and protein kinase Adependent manner, in cultured vascular SMCs of rats.71 Moreover, AM weakened redox-sensitive cellular responses such as the activation of c-Jun amino-terminal kinase (JNK) and gene expression for plasminogen activator inhibitor (PAI)-1, monocyte chemoattractant protein-1, and Nox-1, a component of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.71
Not only the intima and media but also the adventitial layer has been recognized to have a significant role in the process of vascular remodeling. Blood vessels would increase their stiffness if an excessive accumulation of extracellular matrix or proliferation of adventitial fibroblast were to occur. The proliferation of adventitial fibroblasts induced by aldosterone, a factor involved in the fibrosis of cardiovascular tissue, was found to be suppressed by AM, with a concomitant reduction in the activity of extracellular signal-related kinase.39 Additionally in that study, autocrine or paracrine inhibition by AM was proposed, based on the production of AM by the adventitial fibroblasts and on augmented proliferation by the AM receptor antagonists.39 By synthesizing and degrading matrix proteins, adventitial fibroblasts are known to modulate the formation of the extracellular matrix in the adventitia. Our recent experiments showed that AM upregulated the enzymatic activity and protein expression of matrix metalloproteinase-2 (MMP-2), which degrades collagens and elastin, in cultured adventitial fibroblasts of rat aorta possibly via the cAMPprotein kinase A pathway.72 Collectively, these findings suggest a role for AM in modulating adventitial proliferation and extracellular matrix formation.
| Vascular Protective Effects In Vivo |
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Using the first method, we found that prolonged AM infusion for 2 weeks partially inhibited neointimal hyperplasia induced by balloon injury in rat carotid arteries (Figure 4).63 Meanwhile, somewhat conflicting findings were obtained by Shimizu et al, who showed that chronic infusion of the AM antagonist CGRP(837) inhibited neointimal hyperplasia induced by ballooning in rats.73 CGRP(837) is a CGRP receptor antagonist, which has been able to block some, but not all, the actions of AM in relatively short-term experiments.16,20,30,62 However, it has yet to be clarified whether or not this antagonist can block the action of endogenous AM when infused chronically. It should be noted that in our study mentioned above, the prolonged infusion of AM suppressed not only balloon injuryinduced intimal hyperplasia but also the proliferation of fibroblasts and collagen deposition of the adventitia (Figure 4),63 a finding consistent with the in vitro inhibitory effect of AM on the proliferation of cultured adventitial fibroblasts.39 Inhibition of adventitial hyperplasia by AM was confirmed by our study in vivo, in which perivascular fibrosis of coronary arteries of rats infused chronically with angiotensin II was suppressed by coinfusion of AM.64 This effect was accompanied by the suppression of fibroblast activation and transforming growth factor (TGF)-ß1 expression, but not by a significant reduction of blood pressure.64
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In accord with the effect of prolonged infusion of AM, adenovirus-mediated local delivery of the AM gene was shown to inhibit neointimal hyperplasia of carotid arteries after balloon injury in rats.74 Interestingly in that study, endothelial regeneration was more pronounced in rats given the AM gene than in the controls,74 a result consistent with the cell culture experiments, where AM promoted reendothelialization of a wounded monolayer of endothelial cells.67 The inhibition of neointimal hyperplasia by the AM gene delivery was accompanied by an elevation of tissue cGMP levels, suggesting a mechanism involving the NOcGMP pathway.74
Thirdly, vascular protective effects have been suggested by genetic manipulation of the AM gene in mice. Transgenic mice overexpressing the AM gene (AM-Tg) were found to be resistant to neointimal hyperplasia induced by a periarterial cuff placed on the femoral artery.75 This resistance seems also to be mediated by the NOcGMP pathway because it disappeared on administration of L-NAME.75 Moreover, a protective effect of AM was demonstrated by cross-mating apoE knockout (apoE-KO) mice with AM-Tg. The apoE-KO mice overexpressing AM showed a less extensive hypercholesterolemia-induced fatty streak formation with a greater endothelium-dependent vasodilatation, compared with the control apoE-KO mice.75 In contrast to the mice overexpressing AM, heterozygotes of AM knockout mice given angiotensin II and excessive salt showed a more severe perivascular fibrosis and intimal thickening of coronary arteries, compared with their wild-type littermates, despite a similar elevation of blood pressure.76 Based on increases in the production of ROS and in NADPH oxidase expression in the AM knockout mice, the possibility of augmented oxidative stress was raised as the mechanism responsible for the severe vascular lesions.76 Periarterial cuff-induced intimal thickening of the femoral artery was also found to be more severe in the knockout mice, compared with the control mice.77 The enhanced neointimal formation was reversed by delivery of the AM gene and by an NADPH oxidase inhibitor or tempol, a superoxide dismutase mimetic,77 further suggesting augmented oxidative stress in the AM knockout mice.
Lastly in this section, we should mention the effect of AM on the pulmonary vascular bed as a protective action. In addition to the pulmonary vasodilator effect, prolonged subcutaneous infusion of AM was found to inhibit medial thickening of the pulmonary artery of rats with pulmonary hypertension induced by monocrotaline.78 However, when infused intravenously, AM lowers not only pulmonary artery pressure but also systemic blood pressure.24 In an attempt to avoid the effect on the systemic circulation, Nagaya et al administered AM as an aerosol using an ultrasonic nebulizer in rats with pulmonary hypertension.79 Repeated inhalation effectively inhibited medial thickening of pulmonary arteries, reducing pulmonary artery pressure and total pulmonary resistance, without affecting the systemic arterial pressure or heart rate. Furthermore, the same group reported that in patients with idiopathic pulmonary arterial hypertension, inhalation of AM lowered pulmonary artery pressure and resistance, improving exercise tolerance.80 Although the long-term effects need to be examined, this novel approach seems promising for using AM in the treatment of primary pulmonary hypertension, for which few effective medical treatments are currently available.
| Angiogenetic Effect of AM |
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Very recently, AM infusion was shown to enhance the angiogenic potency of implanted bone marrowderived cells by inhibiting apoptosis of the cells. Angiogenesis after transplantation of bone marrowderived mononuclear cells was augmented by AM in rats with hind limb ischemia.84 Similarly in a rat model of cerebral infarction, the angiogenic effect of transplanted mesenchymal stem cells was enhanced by AM infusion in ischemic penumbra of the brain, improving neurological deficits.85 Collectively, it seems likely that AM possesses angiogenic properties, suggesting its potential as a therapeutic tool in the treatment of organ or tissue ischemia.
| Conclusion and Perspective |
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| Acknowledgments |
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Received May 17, 2005; accepted July 11, 2005.
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