Pleiotrophin is an important regulator of the renin–angiotensin system in mouse aorta
Gonzalo HerradónLaura EzquerraTrang NguyenThomas VogtRoderick BronsonInmaculada Silos‐SantiagoThomas F. Deuel
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Pleiotrophin
We have shown that the renin-angiotensin system (RAS) is involved in glucose homeostasis during acute hemorrhage. Since almost all of the physiological actions described for angiotensin II were mediated by AT1 receptors, the present experiments were designed to determine the participation of AT1 receptors in the hyperglycemic action of angiotensin II in freely moving rats. The animals were divided into two experimental groups: 1) animals submitted to intravenous administration of angiotensin II (0.96 nmol/100 g body weight) which caused a rapid increase in plasma glucose reaching the highest values at 5 min after the injection (33% of the initial values, P<0.01), and 2) animals submitted to intravenous administration of DuP-753 (losartan), a non-peptide antagonist of angiotensin II with AT1-receptor type specificity (1.63 µmol/100 g body weight as a bolus, iv, plus a 30-min infusion of 0.018 µmol 100 g body weight-1 min-1 before the injection of angiotensin II), which completely blocked the hyperglycemic response to angiotensin II (P<0.01). This inhibitory effect on glycemia was already demonstrable 5 min (8.9 ± 0.28 mM, angiotensin II, N = 9 vs 6.4 ± 0.22 mM, losartan plus angiotensin II, N = 11) after angiotensin II injection and persisted throughout the 30-min experiment. Controls were treated with the same volume of saline solution (0.15 M NaCl). These data demonstrate that the angiotensin II receptors involved in the direct and indirect hyperglycemic actions of angiotensin II are mainly of the AT1-type.
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Two main classes of angiotensin II receptors, angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors, have been identified by molecular cloning and pharmacological studies [1]. Most of the physiological angiotensin II effects, such as vasoconstriction and fluid homeostasis regulation, have been attributed to AT1 receptor activation [1]. However, there is growing evidence that the AT2 receptor may act as an opponent to the AT1 receptor by exerting opposite effects (e.g. vasodilatation and anti-proliferation) [1]. Consequently, it has been hypothesized that the AT2 receptor is gaining functional importance during selective AT1 receptor blockade, mediating some of the beneficial effects of these compounds by redirecting the available angiotensin II to the AT2 receptor [2]. Does this counterbalance of AT1–AT2 receptor actions also exist with regard to the role of angiotensin II in the development and progresssion of atherosclerosis? For some time, angiotensin II has been known to promote atherosclerotic disease. This effect was initially attributed to an indirect mechanism of blood pressure elevation resulting in haemodynamic changes and lesion formation. However, a number of groups have now demonstrated that angiotensin II exerts direct pro-atherosclerotic actions on the vessel wall, including a stimulation of proinflammatory processes in endothelial cells and monocytes/macrophages, as well as the induction of proliferative and migratory responses in vascular smooth muscle cells [3–5]. Consistently, the infusion of angiotensin II into mice at subpressor doses resulted in a marked formation of atherosclerotic lesions in the aorta of the animals [4]. The blood pressure-independent pro-atherosclerotic actions of angiotensin II are further supported by clinical studies where blockade of angiotensin II responses, either by angiotensin-converting enzyme inhibition or selective AT1 receptor blockade, lowers the risk of cardiovascular end points in the absence of major changes in blood pressure compared to control groups [6,7]. With mounting evidence for a role of angiotensin II in atherosclerosis, it has now become increasingly clear that the AT1 receptor subtype is the major mediator of the pro-atherosclerotic actions of angiotensin II. In experimental studies performed in vitro, AT1 receptor stimulation induces multiple effects involved in atherogenesis, such as monocyte recruitment and migration, activation of endothelial cells, promotion of endothelial dysfunction, augmentation of oxidative stress and proliferation/migration of smooth muscle cells [1,5]. In addition, Wassmann et al. [8] recently showed that deletion of the AT1A receptor in apolipoprotein E (apo E) −/− mice prevents the atheroslcerotic lesion formation underlining the importance of the receptor subtype in this pathology [8]. What is the role of the AT2 receptor in atherosclerosis? In the present issue of the journal, Johansson et al. [9] report on a series of animal experiments using angiotensin II infusion in apoE −/− mice in the absence or presence of selective AT2 receptor blockade with PD123319. The authors used 8-week-old male apoE −/− mice, and infused angiotensin II (0.5 μg/kg per min) ± PD123319 (3 mg/kg per day) for 28 days via a subcutaneously implanted osmotic minipump. The experiments were performed in two different groups of mice receiving either a standard diet or a high cholesterol diet. The overall conclusion from their results is that the AT2 receptor does not play a role in atherogenesis in their model of atherosclerosis. Is this the final answer for the overall actions of the AT2 receptor in atherogenesis? The history of the AT2 receptor in cardiovascular disease should be considered together with that of angiotensin II in atherosclerosis. Covering many aspects of the cardiovascular continuum, the story behind the AT2 receptor has often been much more complex than ‘good’ and ‘bad’, or ‘pro’ and ‘anti’. Is there really no evidence for any function of the AT2 receptor in atherogenesis? Daugherty et al. [10] previously used a similar model to that employed by Johansson et al. [9]. By contrast to the results published here, Daugherty et al. [10] found a marked potentiation of angiotensin II-induced atherogenesis after blockade of the AT2 receptor with PD123319. [10] In line with this data, Wu et al. [11] demonstrated that the AT2 receptor is a major anti-inflammatory mediator in an animal model of vascular injury, which gains more relevance in view of the important role of inflammation in the atherosclerotic process. Taken together, the previously published work has demonstrated specific functions of the AT2 receptor in the atherosclerotic processes that may inhibit the progression of this disease. What are the explanations for the discrepant findings? The authors discuss a number of differences in their models focusing on gender and different breeding stocks of mice. The gender differences are an intriguing and fascinating argument. It has now become increasingly clear that sex hormones and their corresponding receptors are important regulators of cardiovascular pathogenesis, and that they have remained widely unnoticed in previous studies. [12] Therefore, the field of gender aspects in general and, in particular, gender differences in AT2 receptor biology, will become more and more important in the future. Recent studies [13,14] have already shown that estrogen appears to augment AT2 receptor expression and function, which may implicate that the AT2 receptor actions are more prominent in the female mice used by Daugherty et al. [10] than in the male mice used by Johansson et al. [9]. The differences in breeding stocks associated with the presence of potential genetic drifts emphasize a very important point, which has been excellently taken into account in the discussion by Johansson et al. [9]. In certain areas of cardiovascular research, there is a need to be aware of the limitations of the available experimental models, and the conclusions drawn out of these models have to be vigorously embedded in previously published work. By studying one specific model of atherosclerosis, arterial hypertrophy or angiogenesis, one should be careful to extrapolate on the general functions of the AT2 receptor system. The AT2 receptor appears to be an enigmatic receptor mediating a number of contrary effects in the cardiovascular system. However, the protective actions of this receptor still outweigh the deleterious actions in the cardiovascular system, including the effects on atherosclerosis.
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Abstract: An ongoing issue in cardiac pharmacology is whether angiotensin II has direct growth promoting effects on the heart via the angiotensin II type 1 (AT1) receptor. This question has relevance for whether angiotensin-converting enzyme inhibitors and AT1 receptor blockers offer additional benefit in preventing adverse cardiac remodeling in hypertension. In a recent study, 2 strains of mice were infused with angiotensin II. In both, AT1 receptors were deleted in the heart and conduit vessels, but in one, AT1 receptors were also deleted in resistance vessels. Angiotensin II caused hypertrophy and hypertension in the strain lacking AT1 receptors in the heart and conduit vessels, but not in the strain without AT1 receptors in resistance vessels. This finding supports the conclusion that blood pressure is more important in determining cardiac hypertrophy than direct AT1 activation by angiotensin II, when the two are rapidly and simultaneously introduced. Surprisingly, mice with no cardiac AT1 receptor expression developed ventricular dilation and eccentric hypertrophy with pressure overload, in contrast to wild type mice that exhibited concentric hypertrophy, suggesting that cardiac AT1 receptors protect against high blood pressure. This interpretation revives issues related to β–arrestin-biased signaling and mechanosensitivity of AT1 receptors. Synthetic nanobodies, which are based on the variable regions of camelid-derived heavy chain–only antibodies, could be applied to explore the therapeutic potential of exploiting different activation states of AT1 under stress conditions, such as hypertension and heart failure. At the very least, this experimental approach is likely to reveal new facets of AT1 receptor signaling in the heart.
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The rapid expansion of our knowledge of angiotensin receptors has been led by the development of subtype-specific angiotensin II receptor antagonists and by the cloning and sequencing of the ATT receptor in angiotensin II. Although some actions of angiotensin II have been attributed to AT2 subtype receptors, the importance of these binding sites remains elusive. Nonpeptide, AT] -selective antagonists, such as losartan, block virtually all of the well-known effects of angiotensin II in mammalian cells. The effects of losartan are now being confirmed by the rapidly developing class of nonpeptide, ATi-selective angiotensin II receptor antagonists. In rodents, subtypes of the ATT receptor have been cloned and designated AT^ and AT^, but they have not been functionally distinguished. Such isoforms have not been identified for human ATi receptors. Importantly, it now appears that the AT2 receptor has been cloned. The angiotensin receptors undergoing intense study are those in fetal tissue, brain, endothelial cells, and fibroblasts. Angiotensin ll-induced growth and cardiovascular hypertrophy are the focus of broad-based research efforts. The clinical relevance of angiotensin II receptor subtypes is unknown, but there is growing evidence that AT^-selective agents are effective inhibitors of the angiotensin system in humans.
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