Cellular Mechanism of Vasoconstriction Induced by Angiotensin II
2003; Lippincott Williams & Wilkins; Volume: 93; Issue: 11 Linguagem: Inglês
10.1161/01.res.0000105920.33926.60
ISSN1524-4571
AutoresHideo Kanaide, Toshihiro Ichiki, Junji Nishimura, Katsuya Hirano,
Tópico(s)Eicosanoids and Hypertension Pharmacology
ResumoHomeCirculation ResearchVol. 93, No. 11Cellular Mechanism of Vasoconstriction Induced by Angiotensin II Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCellular Mechanism of Vasoconstriction Induced by Angiotensin IIIt Remains To Be Determined Hideo Kanaide, Toshihiro Ichiki, Junji Nishimura and Katsuya Hirano Hideo KanaideHideo Kanaide From the Division of Molecular Cardiology (H.K., J.N., K.H.) and Cardiovascular Medicine (T.I.), Research Institute of Angiocardiology, Graduate School of Medical Sciences, and Kyushu University COE Program on Lifestyle-Related Diseases, Kyushu University, Fukuoka, Japan. , Toshihiro IchikiToshihiro Ichiki From the Division of Molecular Cardiology (H.K., J.N., K.H.) and Cardiovascular Medicine (T.I.), Research Institute of Angiocardiology, Graduate School of Medical Sciences, and Kyushu University COE Program on Lifestyle-Related Diseases, Kyushu University, Fukuoka, Japan. , Junji NishimuraJunji Nishimura From the Division of Molecular Cardiology (H.K., J.N., K.H.) and Cardiovascular Medicine (T.I.), Research Institute of Angiocardiology, Graduate School of Medical Sciences, and Kyushu University COE Program on Lifestyle-Related Diseases, Kyushu University, Fukuoka, Japan. and Katsuya HiranoKatsuya Hirano From the Division of Molecular Cardiology (H.K., J.N., K.H.) and Cardiovascular Medicine (T.I.), Research Institute of Angiocardiology, Graduate School of Medical Sciences, and Kyushu University COE Program on Lifestyle-Related Diseases, Kyushu University, Fukuoka, Japan. Originally published28 Nov 2003https://doi.org/10.1161/01.RES.0000105920.33926.60Circulation Research. 2003;93:1015–1017In this issue of Circulation Research, using mouse large conduit arteries, Zhou et al1 have provided direct evidence that AT1b, a subtype of angiotensin (Ang) II type 1 (AT1) receptors, predominantly mediates contractions induced by Ang II. In Figure 3, when 100 nmol/L Ang II was applied to the abdominal aorta and the femoral artery of knockout mice for AT1a, biphasic responses in tension appeared. Tension rose rapidly and transiently peaked in a few minutes, and then declined to a lower steady level (close to the preapplication level) at 10 to 20 minutes. Thus, Ang II causes a rapid contraction that attenuates significantly after several minutes even in the continued presence of agonist. However, the mechanisms underlying the biphasic response to Ang II are not explained in the report.Stimulation of AT1 receptors leads to activation, via the G protein Gq, of phospholipase C, which hydrolyzes phosphatidylinositol-4,5-bisphosphate to generate inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DG). IP3 triggers the intracellular release of Ca2+, and additional Ca2+ enters the cell from outside due to opening of Ca2+ channels located in the cell membrane. Ca2+/calmodulin-dependent myosin light chain kinase (MLCK) can switch on MLC phosphorylation and tension development. The extent of MLC phosphorylation reflects the activities of both MLCK and MLC phosphatase (MLCP). Thus, at constant Ca2+ and MLCK activity, inhibition of MLCP will cause an increase in MLC phosphorylation and tension, a phenomenon called Ca2+ sensitization. There are two well-described myosin phosphatase inhibitory pathways.2 The first is the RhoA/Rho-kinase pathway that either directly or indirectly acts on the regulatory phosphatase subunit to inhibit phosphatase activity (see Figure). The second is the protein kinase C (PKC)/CPI-17 pathway that inhibits the catalytic subunit of myosin phosphatase. In the latter pathway, PKC inhibits myosin phosphatase, which results in an increase in MLC phosphorylation and tension, and thus, Ca2+ sensitization. Interestingly, as a general model of smooth muscle contraction, it was proposed that PKC stimulation in the sustained phase of contraction results in the phosphorylation of both structural and regulatory components of the filament-actin-desmin fibrillar domain.3 Ang II also activates phospholipase D, which hydrolyzes phosphatidylcholine to generate choline and phosphatidic acid, and the latter is rapidly converted to DG. This pathway is suggested to play a major role in the activation of PKC in the sustained phase of Ang II–induced contraction.4Download figureDownload PowerPointSignal transduction pathways after activation of AT1 with focus on the excitation-contraction coupling in vascular smooth muscle. The stimulation of AT1 activates phospholipase C (PLC) and produces inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DG). IP3 induces Ca2+ release from the intracellular stores through IP3 receptor (IP3R). AT1 also activates Ca2+ influx through channels on plasma membrane. The elevation of cytosolic Ca2+ concentration activates myosin light chain kinase (MLCK) and thereby phosphorylates myosin, which induces smooth muscle contraction. In addition to the PLC-derived DG, DG is also converted from phosphatidic acid produced by phospholipase D (PLD). DG activates protein kinase C (PKC). One of its substrates is a 17-kDa PKC-potentiated inhibitory protein of type 1 protein phosphatase (CPI17), which directly inhibits the activity of myosin light chain phosphatase (MLCP). AT1 also activates the RhoA/Rho-kinase pathway, which inhibits MLCP activity. CPI17 is also a substrate of Rho-kinase. The inhibition of MLCP causes a greater extent of myosin phosphorylation for a given elevation of Ca2+, resulting in the myofilament Ca2+ sensitization. AT1 transactivates EGF receptor and indirectly activates mitogen-activated protein kinase pathway. This pathway is one of the important pathways leading to smooth muscle proliferation and hypertrophy.To investigate the mechanism underlying the Ang II–induced biphasic contractile response, we determined the effects of Ang II on cytosolic Ca2+ concentration ([Ca2+]i) and tension development in the isolated rabbit femoral artery. As in the case of Zhou et al,1 100 nmol/L Ang II elicited a biphasic response of tension accompanied by a similar change of [Ca2+]i, which consisted of an initial transient and a subsequent lower and sustained phase.5 The lower and sustained phase contraction was attributed to a decrease in [Ca2+]i but is not correlated with a change in Ca2+ sensitivity. The decrease in [Ca2+]i was due to an inhibition of Ca2+ influx, but also was possibly due to the activation of Ca2+ extrusion and/or Ca2+ sequestration. Ang II thus has not only a stimulatory but also an inhibitory effect on Ca2+ signaling. Since changes in tension were similar, Ca2+ signaling and homeostasis working in conduit arteries during the stimulation with Ang II in mouse1 might be similar to those in rabbit.5 The precise underlying mechanism in the intracellular signaling network and Ca2+ sensitization for Ang II–induced vasoconstriction remains to be elucidated.By using Ang II analogues, it was demonstrated that the biphasic contractile response (homologous desensitization) was due to the interaction of Ang II with a regulatory site on the Ang II receptor.6 Recently, two subtypes of Ang II receptor designated type 1 (AT1) and type 2 (AT2) have been cloned and belong to the seven-transmembrane type receptor family.7 It is generally accepted that most of the traditionally recognized functions of Ang II such as vasoconstriction, sodium and water retention, and facilitation of adrenergic nerve activity are ascribed to AT1. Production of reactive oxygen species, proliferation of vascular smooth muscle cells, and atherogenesis, which are recent topics in the investigation of the function of Ang II, are also mediated by AT1.8 The physiological role of AT2 is less clearly defined. A growing body of evidence, however, has suggested that the function of AT2 is opposite to AT1 and is protective for the cardiovascular system.9 AT2 has been reported to induce nitric oxide production and inhibit growth.Two isoforms of AT1 subtype are present in the rodent genome (AT1a and AT1b), whereas a single AT1 gene is present in the genome of human, pig, and cow.7 AT1a is widely expressed in rat cardiovascular tissues such as heart, aorta, and kidney.10 In contrast to AT1a, AT1b is predominantly expressed in the adrenal gland, pituitary gland, and testis and weakly expressed in the kidney and brain. The amino acid sequences of AT1a and AT1b are 95% identical.11 AT1a and AT1b are similar in terms of their ligand binding, activation properties, and signaling pathways and are pharmacologically indistinguishable.12 However, the mRNA sequences of noncoding region of AT1a and AT1b show marked differences, which suggest a differential mRNA regulation. In humans with a single AT1 gene, two isoforms of AT1 have also been reported.13 These isoforms are generated through an alternative splicing of exon 3 of human AT1 gene.Although null mice for the angiotensinogen gene and angiotensin-converting enzyme (ACE) gene show hypotension, reduced survival, and marked renal abnormalities, knockout mice for AT1a display only hypotension but not impairments in survival and renal development, suggesting that AT1a does not fully account for the diverse functions of Ang II.14 AT1a knockout mice lacked the pressor response to Ang II infusion15; however, subsequent study showed dose-dependent elevations of blood pressure after treatment with an ACE inhibitor, enalapril, to eliminate endogenous Ang II.16 The elevation of blood pressure was blocked by an AT1 receptor antagonist. These studies suggest that the AT1b receptor also contributes to the pressor response to Ang II in the absence of AT1a, although the relative contribution of AT1b to blood pressure regulation is smaller than that of AT1a. Zhou et al1 showed that contractile response to Ang II is present in the abdominal aorta in AT1a knockout mice that has only AT1b. Losartan, an AT1 antagonist, binds to both AT1a and AT1b with similar affinity and extent of inhibition. In the abdominal aorta in AT1a knockout mice, the contractile response to Ang II was inhibited by losartan, confirming the role of AT1b. It is of interest that normal blood pressure and pressor response to Ang II was reported in AT1b-deficient mice.17 It was somewhat surprising that the dominant isoform of mouse AT1 in the aorta was AT1b, because AT1a is the main isoform of rat aorta and cultured rat vascular smooth muscle cells. An early report that studied differential expression of AT1a and AT1b in mice failed to examine the aorta.18Two alternatively spliced human AT1 isoforms are expressed in the aorta.19 However, the exact distribution of these isoforms in the human aorta or arteries has not been investigated. Human AT1 isoforms differ slightly in the binding affinity to Ang II, Ca2+ mobilization, and IP3 production in response to Ang II. These human AT1 isoforms are, however, pharmacologically indistinguishable, and no apparent difference in signaling mechanisms has been reported, indicating that they are qualitatively similar. It is not clear, therefore, whether the response to Ang II and the dominant receptor isoform differ in a different portion of the human aorta or arteries. Based on our current knowledge regarding the human AT1 isoforms, selective inhibition of these human AT1 isoforms may not show better clinical benefit than recently developed AT1 antagonists that bind to both isoforms.In summary, the study by Zhou et al1 clearly revealed the predominant role for AT1b in the vasoconstriction of conduit arteries, using wild-type and AT1a knockout mice. It is necessary to provide new insights into molecular events in intracellular signaling associated with vasoconstriction induced by Ang II, because it is still an important therapeutic target in the pathophysiology of cardiovascular disease.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.AcknowledgmentsThis study was supported in part by the grant from the 21st Century COE Program and Grants-in-Aid for Scientific Research (Nos. 13470149, 14657174, 14570675, 15590758) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, by the Research Grant for Cardiovascular Diseases (13C-4) from the Ministry of Health, Labor and Welfare, Japan, and by grants from the Japan Space Forum and the Naito Foundation.FootnotesCorrespondence to Hideo Kanaide, MD, PhD, Professor, Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, Japan 812-8582. 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