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PubMed1996

Modulation of membrane potential and ionic currents by the AT1 and AT2 receptors of angiotensin II.

Angiotensin II, the principal effector of the renin-angiotensin system, modulates various ionic currents. Its effects on potassium currents, including outward transient potassium current, the inward or outward rectifiers, as well as Ca(2+)- activated potassium currents, is well described. Other ionic currents, such as voltage-dependent calcium currents, cationic or chloride currents, are also altered by the hormone. All these effects provoke changes in membrane potential, such as modulation of action potential firing or resting membrane potential and control intracellular calcium concentration. Summarized here are the results obtained on these membrane electrical properties using electrophysiological recordings.

Action Potentials↗

PubMed2003

Inflammation and angiotensin II.

Angiotensin II (AngII), the major effector peptide of renin-angiotensin system (RAS), is now recognized as a growth factor that regulates cell growth and fibrosis, besides being a physiological mediator restoring circulatory integrity. In the last few years, a large number of experimental studies has further demonstrated that AngII is involved in key events of the inflammatory process. Here, we summarize the wide variety of AngII functions and discuss them in relation with the inflammatory cascade. AngII increases vascular permeability (via the release of prostaglandins and vascular endothelial cell growth factor or rearrangement of cytoskeletal proteins) that initiates the inflammatory process. AngII could contribute to the recruitment of inflammatory cells into the tissue through the regulation of adhesion molecules and chemokines by resident cells. Moreover, AngII could directly activate infiltrating immunocompetent cells, including chemotaxis, differentiation and proliferation. Recent data also suggest that RAS activation could play a certain role even in immunologically-induced inflammation. Transcriptional regulation, predominantly via nuclear factor-kappaB (NF-kappaB) and AP-1 activation, and second mediator systems, such as endothelin-1, the small G protein (Rho) and redox-pathways are shown to be involved in the molecular mechanism by which AngII exerts those functions. Finally, AngII participates in tissue repair and remodeling, through the regulation of cell growth and matrix synthesis. In summary, recent data support the hypothesis that RAS is key mediator of inflammation. Further understanding of the role of the RAS in this process may provide important opportunities for clinical research and treatment of inflammatory diseases.

Angiotensin II↗

PubMed2005

Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II.

Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.

Angiotensin II↗

PubMedDate not supplied

Effects of angiotensin II and its fragments: angiotensin II(3-8)-hexapeptide and angiotensin II(4-8)-pentapeptide on retrieval in passive avoidance situation in rats chronically treated with ethanol.

Rats with impaired retrieval of passive avoidance behavior induced by chronic (9 weeks) administration of ethanol were studied. Angiotensin II (AII) and its fragments: AII(3-8) and AII(4-8), administered (icv, 2.0 micrograms) on the third day after ethanol withdrawal, neutralized the toxic effect of ethanol. Furthermore, the peptide AII(3-8) also gave an improvement in retrieval of the capability to perform simple behavioral tasks as it did in the control group in rats chronically pretreated with alcohol.

Angiotensin II↗

PubMed2000

The effects of thiazolidinediones on vascular smooth muscle cell activation by angiotensin II.

Angiotensin II (Ang II) stimulates the activation of extracellular signal-regulated kinase (ERK), a subgroup of the mitogen-activated protein kinase (MAPK) family, in cultured vascular smooth muscle cells (VSMC). This ERK activation was recently shown to be a critical regulatory factor for Ang II-mediated migration and growth. It has been demonstrated that the thiazolidinedione troglitazone (TRO) blocked Ang II-induced DNA synthesis and migration in VSMC. Here we provide evidence for TRO to inhibit Ang II-induced ERK activation which was suggested to constitute the mechanism by which this agent blocks Ang II-induced VSMC growth and migration. We have found that pretreatment with PD98059, which selectively blocks the activity of ERK pathway at the level of MAPK kinase, decreased Ang II-induced AP-1 activation and that TRO is capable of inhibiting Ang II-induced AP-1 activation. On the other hand, the other thiazolidinediones pioglitazone (PIO) and rosiglitazone (ROSI) had little effect on Ang II-induced activation of ERK or AP-1, suggesting the inhibitory effects of TRO on VSMC activation by Ang II be independent of the peroxisome proliferator-activated receptor-gamma (PPARgamma) for which thiazolidinediones are ligands. Ang II-induced ERK activation was inhibited by protein kinase C (PKC)-specific inhibitor GF109203X, while TRO was also able to block PKC activator phorbol 12 myristate 13-acetate (PMA)-induced ERK activation. Accordingly, TRO may inhibit Ang II-induced MAPK activation at least partly by an inhibition of PKC. These results support the assumption that by targeting MAPK activation, TRO may inhibits the critical signaling steps leading to restenosis and atherosclerosis that may result in part from dysregulated VSMC growth and migration induced by Ang II.

Angiotensin II↗

PubMed2003

Prostaglandins but not nitric oxide protect renal medullary perfusion in anaesthetised rats receiving angiotensin II.

Angiotensin II (Ang II) fails to constrict renal medullary vasculature, possibly due to the counteraction of local vasodilators, such as prostaglandins or nitric oxide (NO). The effects of exogenous Ang II on intrarenal circulation were determined in anaesthetised rats that were untreated or pretreated with indomethacin (Indo) or L-NAME. The total renal blood flow (RBF), representing cortical perfusion, and outer and inner medullary blood flow (OMBF and IMBF) were measured. In untreated rats, Ang II decreased RBF in a dose dependent manner. Intravenous administration of 30 ng kg-1 min-1 Ang II decreased RBF by 38 % and OMBF by 9 % (both significant); IMBF was unaffected. Indo (5 mg kg-1 I.V.) significantly and similarly decreased OMBF and IMBF without affecting RBF. Ang II decreased IMBF by 27 % in Indo-pretreated rats, but caused no change in rats without pretreatment. The decreases in OMBF and RBF were comparable with or without Indo pretreatment. Inhibition of NO synthesis with L-NAME (0.6 mg kg-1 I.V.) significantly decreased RBF, OMBF and IMBF. Ang II infusion into L-NAME-pretreated rats induced a further significant decrease in RBF and OMBF without changing IMBF. We conclude that within the inner medulla, but not the outer medulla or cortex, prostaglandins effectively counteract the vasopressor effect of circulating Ang II.

Angiotensin II↗

PubMed2004

Angiotensin II and angiotensin-(1-7) inhibit the inner cortex Na+ -ATPase activity through AT2 receptor.

In the present paper, the modulation of the basolateral membrane (BLM) Na+ -ATPase activity of inner cortex from pig kidney by angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) was evaluated. Ang II and Ang-(1-7) inhibit the Na+ -ATPase activity in a dose-dependent manner (from 10(-11) to 10(-5) M), with maximal effect obtained at 10(-7) M for both peptides. Pharmacological evidences demonstrate that the inhibitory effects of Ang II and Ang-(1-7) are mediated by AT2 receptor: The effect of both polypeptides is completely reversed by 10(-8) M PD 123319, a selective AT2 receptor antagonist, but is not affected by either (10(-12) - 10(-5) M) losartan or (10(-10)-10(-7) M) A779, selective antagonists for AT1 and AT(1-7) receptors, respectively. The following results suggest that a PTX-insensitive, cholera toxin (CTX)-sensitive G protein/adenosine 3',5'-cyclic monophosphate (cAMP)/PKA pathway is involved in this process: (1) the inhibitory effect of both peptides is completely reversed by 10(-9) M guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS; an inhibitor of the G protein activity), and mimicked by 10(-10) M guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS; an activator of the G protein activity); (2) the effects of both peptides are mimicked by CTX but are not affected by PTX; (3) Western blot analysis reveals the presence of the Gs protein in the isolated basolateral membrane fraction; (4) (10(-10)-10(-6) M) cAMP has a similar and non-additive effect to Ang II and Ang-(1-7); (5) PKA inhibitory peptide abolishes the effects of Ang II and Ang-(1-7); and (6) both angiotensins stimulate PKA activity.

Adjuvants, Immunologic↗

PubMed2001

Responses of fetal ovine systemic and umbilical arteries to angiotensin II.

Angiotensin II (ANG II) contracts umbilical arteries and has been hypothesized to regulate fetal blood pressure primarily by altering umbilical vascular resistance. To determine whether systemic arteries in term fetal sheep are sensitive to ANG II, isometric contraction of endothelium-intact isolated fetal renal, mesenteric, and umbilical arteries in response to ANG II was studied. ANG II (10(-7) M) elicited contractile responses in all three vessels (43 +/- 8%, 99 +/- 21%, and 105 +/- 5% of the maximal response seen with 90 mM KCl for renal, mesenteric, and umbilical arteries, respectively). The time course of the contractile responses differed among the vessels: renal and mesenteric arteries exhibited rapid transient contraction followed by relaxation, whereas umbilical artery displayed a more slowly developing but sustained contraction (1 +/- 0%, 3 +/- 1%,and 93 +/- 4% of maximal contractile response at 5 min, for renal, mesenteric, and umbilical arteries, respectively). The AT1 receptor antagonist, losartan (10(-6) M), abolished contractile responses in renal and mesenteric arteries but only slowed the contraction in umbilical artery in response to ANG II and had no effect on maximal tension. AT2 receptor blockade (PD 123319, 10(-7) M) had no significant effect on the response to ANG II in any vessel. Indomethacin (10(-6) M) significantly potentiated contraction to ANG II in renal and mesenteric but not umbilical arteries. Northern and Western blot analyses demonstrated the presence of AT1 mRNA and protein in all three vessels. Immunostaining for the AT1 receptor was present in endothelium and the tunica media. These findings demonstrate the AT1 receptor is present and functionally active in fetal systemic arteries and are consistent with previous findings that the umbilical circulation displays a greater responsiveness to ANG II than the systemic vasculature.

Angiotensin II↗

PubMed1988

Norepinephrine uptake by rat jejunum: modulation by angiotensin II.

Angiotensin II (ANG II) is believed to stimulate sodium and water absorption from the small intestine by enhancing sympathetic nerve transmission. This study is designed to determine whether ANG II can enhance sympathetic neurotransmission within the small intestine by inhibiting norepinephrine (NE) uptake. Intracellular NE accumulation by rat jejunum was concentration dependent and resolved into high- and low-affinity components. The high-affinity component (uptake 1) exhibited a Michaelis constant (Km) of 1.72 microM and a maximum velocity (Vmax) of 1.19 nmol.g-1.10 min-1. The low-affinity component (uptake 2) exhibited a Km of 111.1 microM and a Vmax of 37.1 nmol.g-1.10 min-1. Cocaine, an inhibitor of neuronal uptake, inhibited the intracellular accumulation of label by 80%. Treatment of animals with 6-hydroxydopamine, which depletes norepinephrine from sympathetic terminals, also attenuated NE uptake by 60%. Thus accumulation within sympathetic nerves constitutes the major form of [3H]NE uptake into rat jejunum. ANG II inhibited intracellular [3H]NE uptake in a concentration-dependent manner. At a dose of 1 mM, ANG II inhibited intracellular [3H]NE accumulation by 60%. Cocaine failed to potentiate the inhibition of [3H]NE uptake produced by ANG II. Thus ANG II appears to prevent [3H]NE accumulation within rat jejunum by inhibiting neuronal uptake.

Angiotensin II↗

PubMed1999

Angiotensin II decreases neuronal delayed rectifier potassium current: role of calcium/calmodulin-dependent protein kinase II.

Angiotensin II (Ang II) acts at specific receptors located on neurons in the hypothalamus and brain stem to elicit alterations in blood pressure, fluid intake, and hormone secretion. These actions of Ang II are mediated via Ang II type 1 (AT1) receptors and involve modulation of membrane ionic currents and neuronal activity. In previous studies we utilized neurons cultured from the hypothalamus and brain stem of newborn rats to investigate the AT1 receptor-mediated effects of Ang II on neuronal K+ currents. Our data indicate that Ang II decreases neuronal delayed rectifier (Kv) current, and that this effect is partially due to activation of protein kinase C (PKC), specifically PKCalpha. However, the data also indicated that another Ca2+-dependent mechanism was also involved in addition to PKC. Because Ca2+/calmodulin-dependent protein kinase II (CaM KII) is a known modulator of K+ currents in neurons, we investigated the role of this enzyme in the AT1 receptor-mediated reduction of neuronal Kv current by Ang II. The reduction of neuronal Kv current by Ang II was attenuated by selective inhibition of either calmodulin or CaM KII and was mimicked by intracellular application of activated (autothiophosphorylated) CaM KIIalpha. Concurrent inhibition of CaM KII and PKC completely abolished the reduction of neuronal Kv by Ang II. Consistent with these findings is the demonstration that Ang II increases CaM KII activity in neuronal cultures, as evidenced by increased levels of autophosphorylated CaM KIIalpha subunit. Last, single-cell reverse transcriptase (RT)-PCR analysis revealed the presence of AT1 receptor-, CaM KIIalpha-, and PKCalpha subunit mRNAs in neurons that responded to Ang II with a decrease in Kv current. The present data indicate that the AT1 receptor-mediated reduction of neuronal Kv current by Ang II involves a Ca2+/calmodulin/CaM KII pathway, in addition to the previously documented involvement of PKC.

Angiotensin II↗

PubMed2007

Exercise training prevents arterial baroreflex dysfunction in rats treated with central angiotensin II.

Angiotensin II (Ang II)-induced arterial baroreflex dysfunction is associated with superoxide generation in the brain. Exercise training (EX) improves baroreflex function and decreases oxidative stress in cardiovascular diseases linked to elevated central Ang II. The aim of this study was to determine whether previous EX prevents baroreflex impairment caused by central administration of exogenous Ang II via an Ang II-superoxide mechanism. Four groups of rats were used: non-EX artificial cerebrospinal fluid infused, non-EX Ang II infused, EX artificial cerebrospinal fluid infused, and EX Ang II infused. Rats were treadmill trained for 3 to 4 weeks and subjected to intracerebroventricular infusion of Ang II over the last 3 days of EX. Twenty-four hours after the end of EX, the arterial baroreflex was assessed in anesthetized rats. Compared with non-EX artificial cerebrospinal fluid-infused rats, Ang II significantly decreased baroreflex sensitivity (maximum gain: 3.0+/-0.2% of maximum per millimeter of mercury versus 1.6+/-0.1% of maximum per millimeter of mercury; P<0.01), which was abolished by acute intracerebroventricular infusion of the Ang II type 1 receptor antagonist losartan and the reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin. EX prevented the decrease in baroreflex sensitivity and downregulated Ang II type 1 receptor and NADPH oxidase subunit protein expression in the paraventricular nucleus of Ang II-infused rats. Finally, EX decreased superoxide production in the paraventricular nucleus of Ang II-infused rats. These results indicate that EX improves arterial baroreflex function in conditions of high brain Ang II, which is mediated by the central Ang II type 1 receptor and associated with a reduction in central oxidative stress.

Angiotensin II↗

PubMed2002

TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II.

Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-beta1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-beta1-deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang II treatment. In contrast, Ang II-treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II-treated wild-type mice but unchanged in Ang II-treated TGF-beta1-deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II-treated mice. Atrial natriuretic factor expression was approximately 6-fold elevated in Ang II-treated wild-type, but not TGF-beta1-deficient mice. However, the alpha- to beta-myosin heavy chain switch did not occur in Ang II-treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-beta1. The Ang II effect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-beta1 is an important mediator of the hypertrophic growth response of the heart to Ang II.

Angiotensin II↗

PubMed2005

Retrieval improvement is induced by water shortage through angiotensin II.

Angiotensin II (ANGII) has an evolutionary preserved role in determining adaptative responses to water-shortages. In addition, it has been shown to modulate diverse phases of memory. Still, it is not clear whether ANGII improves or spoils memory. We demonstrated that endogenous angiotensins enhance consolidation of a long-term associative memory in the crab Chasmagnathus and that water shortage improves memory consolidation through brain ANGII actions. Here, we show that weakly trained crabs, when water-deprived, exhibit enhanced retrieval. Subsequently, memory retention is indistinguishable from that of strongly trained crabs. ANGII, but not angiotensin IV, is a necessary and sufficient condition for such enhancing effect. We conclude that ANGII released due to water shortage leads to enhanced memory retrieval. Thus, it seems that ANGII has an evolutionary preserved role as a multifunction coordinator that enables an adaptative response to water-shortage. The facilitation of memory consolidation and retrieval would be among those coordinated functions.

Adaptation, Physiological↗

PubMed1996

Renal accumulation of circulating angiotensin II in angiotensin II-infused rats.

Previous studies have demonstrated that low-dose angiotensin II (Ang II) infusion for 14 days mimics two-kidney, one clip Goldblatt hypertension and increases intrarenal Ang II levels. The objective of the present study was to determine whether the augmented intrarenal Ang II is due to intrarenal accumulation of the infused Ang II and/or to an increase in intrarenal formation of endogenous Ang II. Male Sprague-Dawley rats were uninephrectomized and divided into three groups: control (N=6), those infused with [Ile5]Ang II (endogenous form) (N=6), and those infused with [Val5]Ang II (n=8). [Ile5]Ang II or [Val5]Ang II was infused at 40 ng/min via an osmotic minipump implanted subcutaneously. By day 12, systolic blood pressure increased significantly in both [Val5]Ang II-infused rats (197 +/- 7 mm Hg) and [Ile5]Ang II-infused rats (173 +/- 3 mm Hg). Blood and kidney samples were harvested, subjected to high-performance liquid chromatography to separate [Val5]Ang II from [Ile5]Ang II, and then measured by radioimmunoassay. Plasma renin activity was markedly suppressed in both [Ile5]Ang II- and [Val5]Ang II-infused rats. Plasma Ang II levels were elevated in rats infused with both [Ile5]Ang II (121 +/- 24 fmol/mL) and [Val5]Ang II (119 +/- 14 fmol/mL) compared with controls (69 +/- 15 fmol/mL). Both [Ile5]Ang II- and [Val5]Ang II-infused rats exhibited an enhancement of total intrarenal Ang II. Only [Ile5]Ang II (358 +/- 53 fmol/g) was detected in the kidneys of rats infused with -Ile5-Ang II. In [Val5]Ang II-infused rats, a significant portion of total renal Ang II (371 +/- 57 fmol/g) was in the form of [Val5]Ang II (256 +/- 44 fmol/g). Renal [Ile5]Ang II levels were maintained in the [Val5]Ang II-infused rats (116 +/- 15 fmol/g) compared with control rats (116 +/- 11 fmol/g) despite marked suppression of renin release. These results support the hypothesis that infused circulating ANG II is bound to receptor or taken up intrarenally in a manner that protects against degradation.

Angiotensin II↗

PubMed1976

[Sodium release from tissue paracellular space under the influence of angiotensin II].

Angiotensin II added in vitro in concentration 3-10(-10) M increased the sodium release from the aorta wall, myocardium, and skin in the rat. The action persisted at 2 degrees C and in presence of monoiodacetate. Sodium loading increased the sensitivity of aorta to the action of the angiotensin. The angiotensin-induced sodium release seems to be a step towards the myotropic action of the peptide.

Angiotensin II↗

PubMed2006

Effects of specific endothelin-1 receptor antagonists on proliferation and fibronectin production of glomerular mesangial cells stimulated with Angiotensin II.

Angiotensin II (Ang-II) is a potent vasoactive hormone, which plays an important role in the pathogenesis of glomerulosclerosis. Ang-II activates many cytokine systems in the kidney. Recent studies indicate that Ang-II is closely related to the activation of the endothelin-1 (ET-1) system. The present study was designed to measure the [H3]-thymidine uptake and fibronectin production of cultured rat mesangial cells stimulated with Ang-II, and to evaluate the effects of specific ET-1 receptor antagonists, BQ123 (type A receptor antagonist) and IRL1038 (type B receptor antagonist) on the cells. ET-1 was measured by radioimmunoassay and fibronectin by Western blot analysis. The results were as follows: (1) Ang-II enhanced ET-1 production, [H3]-thymidine uptake, number of cells, and fibronectin production of mesangial cells; (2) all the baseline [H3]-thymidine uptake, number of cells, and fibronectin production of mesangial cells can be partly suppressed by BQ123, but not by IRL1038; (3) the increment of Ang-II-enhanced number of cells can be partly suppressed by BQ123, but not by IRL1038; and (4) the increment of Ang-II-enhanced fibronectin production can be partly suppressed by both BQ123 and IRL1038. Our results indicate that Ang-II is an active stimulant for the proliferation and fibronectin production of mesangial cells, and the effect is partly suppressed mainly by ET-1 type A receptor antagonists.

Angiotensin II↗

PubMed1994

Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II.

Angiotensin II (AII) receptors are known to interact with two distinct guanine nucleotide binding proteins, Gq/11 and Gi, in rat adrenal glomerulosa cells to activate phospholipase C and to inhibit adenylate cyclase, respectively. However, in cultured bovine glomerulosa cells AII potentiates rather than inhibits the stimulatory effect of adrenocorticotropin (ACTH) on cAMP levels. This effect of AII was partially mimicked by phorbol 12-myristate 13-acetate (PMA) and was partially inhibited by staurosporine or depletion of protein kinase C but was unaffected by pertussis toxin treatment. No potentiation was detectable in disrupted cells or in membrane preparations. In intact glomerulosa cells, treatment with cyclosporin A or FK506 completely inhibited AII- or PMA-induced potentiation of cAMP production without affecting the response to ACTH. In COS-7 cells transfected with the rat AT1 receptor, AII caused 2-3-fold enhancement of the ACTH-induced cAMP response, an effect that was partially reproduced by PMA. These potentiating actions of AII and PMA were prevented by preincubation with cyclosporin A or FK506, and the latter effect was abolished by rapamycin. These results implicate the Ca2+- and calmodulin-dependent protein phosphatase, calcineurin, in AII-induced enhancement of adenylate cyclase activity in both adrenal glomerulosa and transfected COS-7 cells. The finding that AII enhances ACTH-stimulated production of cAMP by a second messenger-mediated mechanism that involves the participation of calcineurin reveals an additional mode of cross-talk between pathways activated by Ca(2+)-mobilizing and cAMP-generating receptors.

Adrenocorticotropic Hormone↗

PubMed2005

Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II.

Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis. Herein, we describe a novel transcription mechanism through which Ang II inhibits macrophage expression of the ATP-binding cassette transporter A1 (ABCA1), a key regulator of reverse cholesterol transport. We demonstrate that chronic Ang II infusion substantially promotes macrophage infiltration, foam cell formation, and atherosclerosis in low-density lipoprotein receptor-deficient mice and significantly reduces ABCA1 expression in peripheral macrophages. Administration of the Ang II type 1 receptor blocker valsartan inhibited Ang II-induced ABCA1 mRNA repression, macrophage cholesterol accumulation, and atherosclerosis. Ang II treatment reduced ABCA1 promoter activity of in vitro cultured mouse peritoneal macrophages, inducing fos-related antigen 2 (Fra2) protein binding to an ABCA1 promoter E-box motif, a site known to negatively regulate macrophage ABCA1 transcription. Valsartan pretreatment blocked Fra2 binding to the ABCA1 promoter, and Fra2 small interfering RNA pretreatment attenuated Ang II-mediated ABCA1 transcriptional inhibition, confirming the role of Fra2 in this process. This new evidence suggests that Ang II, a well-known proinflammatory and pro-oxidative factor, alters macrophage cholesterol homeostasis by repressing ABCA1 to promote foam cell formation and atherosclerosis.

ATP Binding Cassette Transporter 1↗