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Nitro-oleic acid inhibits angiotensin II-induced hypertension
Open accessAbstract
Rationale: Nitro-oleic acid (OA-NO 2) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO 2 exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature. Objective: The present study sought to investigate the protective role of OA-NO 2 in angiotensin (Ang) II–induced hypertension. Methods and Results: We show that systemic administration of OA-NO 2 results in a sustained reduction of Ang II–induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO 2 significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (AT 1 R)-mediated signaling because vascular contraction by other G-protein–coupled receptors is not altered in response to OA-NO 2 treatment. From the mechanistic viewpoint, OA-NO 2 lowers Ang II–induced hypertension independently of peroxisome proliferation-activated receptor (PPAR)γ activation. Rather, OA-NO 2, but not OA, specifically binds to the AT 1 R, reduces heterotrimeric G-protein coupling, and inhibits IP 3(inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor. Conclusions: These results demonstrate that OA-NO 2 diminishes the pressor response to Ang II and inhibits AT 1 R-dependent vasoconstriction, revealing OA-NO 2 as a novel antagonist of Ang II–induced hypertension.
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TL;DR
Nitro-oleic acid (OA-NO2) lowers angiotensin II (Ang II)-induced hypertension and preexisting hypertension in mice, while its non-nitrated counterpart oleic acid does not. Mechanistically, OA-NO2 adducts the AT1R without blocking Ang II binding, uncouples G-protein signaling, and inhibits downstream IP3 and calcium mobilization.
Key findings
- Systemic OA-NO2 (5 mg/kg/day) reduced Ang II-induced increases in systolic BP by ~15 mmHg and diastolic BP by ~12 mmHg compared with OA or vehicle, without apparent heart-rate changes.
- In isolated rat mesenteric vessels, OA-NO2 at 2.5 μmol/L produced ~50% reduction of Ang II-mediated vasoconstriction at 10−7 mol/L, and 5 μmol/L almost completely abolished Ang II contraction; responses to phenylephrine and endothelin-1 were not affected.
- OA-NO2 lowered Ang II-induced hypertension independently of PPARγ: GW9662 did not reverse the effect, and OA-NO2 persistently reduced Ang II-mediated BP elevation by ~10 mmHg with or without GW9662, whereas rosiglitazone’s ~7 mmHg BP reduction was antagonized by GW9662.
- OA-NO2 bound AT1R with a ~20-fold increase of adducted OA-NO2 in AT1R-expressing cells versus controls, did not interfere with Ang II binding, reduced AT1R–Gαq11 coupling, and inhibited Ang II-induced IP3 and calcium mobilization; 2.5 μmol/L OA-NO2 reduced the fura-2 ratio induced by Ang II by 75%, while 1 μmol/L losartan completely inhibited it.
Methods
- Mice were implanted with osmotic minipumps for OA-NO2 or OA at 5 mg/kg/day and Ang II at 500 ng/kg/min; BP was measured by radiotelemetry and by in vivo carotid catheter tracing, with jugular vein delivery of OA/OA-NO2 and the PPARγ inhibitor GW9662.
- Second-order rat mesenteric arteries were mounted on a myograph, pretreated with OA-NO2 or OA at 2.5 and 5 μmol/L, then contracted with Ang II, phenylephrine, or endothelin-1.
- AT1R binding/adduction was assessed in HEK293 cells overexpressing AT1R using trans-alkylation and HPLC-MS/MS, biotin-labeled OA-NO2 immunoprecipitation, Gαq11 coupling assays, IP3 measurement, and fura-2 calcium imaging.
Limitations
- The paper states that mechanisms underlying nitrated lipid production, structural isomer distributions, the nitrated fatty acid-susceptible proteome, and detailed signaling actions remain incompletely characterized.
- The paper states that Ang II infusion did not significantly change free nitroalkenes in plasma (data not shown) and that local generation of nitrated fatty acids within the vasculature in response to Ang II cannot be excluded.
- The paper states that further studies, including biochemical and crystallographic approaches, are needed to dissect how electrophilic fatty acid derivatives reduce Ang II-mediated hypertension; evident from the text, the mechanistic work relies heavily on HEK293 overexpression systems and ex vivo rodent vessels, with no human data reported.
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In the paper
“without any apparent changes in the heart rate (Online Figure I).”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Results > OA-NO2 reduces Ang II-induced hypertension
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, GW9662 administration (10 mg/kg) compared to vehicle treated mice at the same infusion rate did not attenuate BP increases after Ang II challenge (Figure 4 and Online Figure II).”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Results > OA-NO2 reduction of Ang II-induced hypertension is a PPARγ independent phenomenon
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We show that systemic administration of OA-NO2 results in a sustained reduction of Ang II-induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion.”
- Also stated in: § OA-NO2 reduces Ang II-induced hypertension · plain
“Under these experimental conditions, OA-NO2 but not OA results in a dose-dependent reduction of BP to the preexisting Ang II-induced hypertension (Figure 2F).”
- Also stated in: § Discussion · boosted
“In summary, this is the first demonstration that OA-NO2 has a long-lasting impact on hypertension induced by Ang II infusion and exerts a significant BP lowering effect on preexisting hypertension.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § OA-NO2 reduces Ang II-induced hypertension · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“inhibits IP3 and calcium mobilization”
- Also stated in: § OA-NO2 interferes with G-protein coupling to the AT1R and prevents Ang II-mediated contractile responses in vascular smooth muscle cells (VSMC) · plain
“Competitive radioreceptor analysis showed that OA-NO2, but not OA, reduced Ang II-induced intracellular inositol-1,4,5-trisphosphate (IP3) mobilization (Figure 6C).”
- Also stated in: § OA-NO2 interferes with G-protein coupling to the AT1R and prevents Ang II-mediated contractile responses in vascular smooth muscle cells (VSMC) · plain
“Accordingly, we show a dose-dependent inhibition of Ang II-mediated increase in intracellular calcium mobilization ([Ca2+]i) upon OA-NO2 treatment, as determined by fluorescence imaging of fura-2 (Figure 6D).”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § OA-NO2 interferes with G-protein coupling to the AT1R and prevents Ang II-mediated contractile responses in vascular smooth muscle cells (VSMC) · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Figure 4D, OA-NO2 similarly diminished Ang II-dependent vasoconstriction with or without PPARγ antagonism by GW9662 treatment.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Results > OA-NO2 reduction of Ang II-induced hypertension is a PPARγ independent phenomenon
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reduces heterotrimeric G-protein coupling”
- Also stated in: § OA-NO2 interferes with G-protein coupling to the AT1R and prevents Ang II-mediated contractile responses in vascular smooth muscle cells (VSMC) · plain
“OA-NO2 but not OA significantly reduced AT1R coupled to the immunoprecipitated Gαq11 after 1 min stimuli with Ang II (100 nmol/L) (Figure 6A and 6B).”
- Also stated in: § What New Information Does This Article Contribute? · plain
“OA-NO2 reduces heterotrimeric G-protein coupling to the AT1R and inhibits downstream signaling.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § OA-NO2 interferes with G-protein coupling to the AT1R and prevents Ang II-mediated contractile responses in vascular smooth muscle cells (VSMC) · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, at an infusion rate of 5mg/kg/day, reduction of Ang II-mediated hypertension is afforded by the nitrated but not free form of OA.”
- Also stated in: § Discussion · hedged
“Furthermore, comparative analysis with the inclusion of the OA-treated group, as the non-nitrated counterpart for OA-NO2 also indicates that OA alone at the dosage used in the present study did not reduce Ang II-mediated hypertension in contrast to previous studies indicating that OA or related species might be hypotensive37.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Discussion · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“From the mechanistic viewpoint, OA-NO2 lowers Ang II-induced hypertension independently of peroxisome proliferation-activated receptor-γ (PPARγ) activation.”
- Also stated in: § OA-NO2 reduction of Ang II-induced hypertension is a PPARγ independent phenomenon · hedged
“This series of experiments indicate that PPARγ activation by OA-NO2 is not the major mechanism involved in OA-NO2 antagonism of both Ang II-mediated hypertension and vasoconstriction.”
- Also stated in: § Discussion · boosted
“Taking into account that OA-NO2 specifically reduced Ang II-mediated vascular contractility but did not interfere with the contractile properties of ET-1 and PE, it can be concluded that PPARγ activation by OA-NO2 is not the major mechanism involved in OA-NO2 effects on AngII-induced hypertension.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § OA-NO2 reduction of Ang II-induced hypertension is a PPARγ independent phenomenon · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“without inhibiting Ang II binding to the receptor.”
- Also stated in: § OA-NO2 does not interfere with Ang II binding to the receptor · plain
“Unlike the ARB losartan, that inhibits Ang II binding to AT1R, neither OA-NO2 nor OA affected binding of radio-labeled Ang II to its receptor (Figure 5E).”
- Also stated in: § Discussion · hedged
“However, adduction of the AT1R by OA-NO2 did not interfere with Ang II binding to its receptor, suggesting that the molecular interactions between OA-NO2 and AT1R are unlikely similar to typical competitive inhibitors of AT1R44, 45.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § OA-NO2 does not interfere with Ang II binding to the receptor · plain
In the paper
“In the context of the vasculature, OA-NO2 inhibits neointimal hyperplasia19 and exerts vasorelaxation of preconstricted aortic rings20.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Introduction
What the sources say
- Not checked yetcites [20] Lim DG Sweeney S Bloodsworth A White CR Chumley PH Krishna NR Schopfer F O’Donnell VB Eiserich JP Freeman BA Nitrolinoleate, a nitric oxide-derived mediator of cell function: synthesis, characterization, and vasomotor activity Proc Natl Acad Sci U S A 2002 99 15941 15946 12444258 PMC138544 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 5
- The quote only partly states this claim. 2
- Probably not a substantial claim. 3
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rather, OA-NO2, but not OA, specifically binds to the AT1R, reduces heterotrimeric G-protein coupling and inhibits IP3 and calcium mobilization, without inhibiting Ang II binding to the receptor.”
- Also stated in: § OA-NO2 forms covalent adducts with the AT1R receptor · boosted
“Thus, two independent approaches showed that AT1R is a relevant cellular target of OA-NO2 alkylation.”
- Also stated in: § Discussion · boosted
“Notably, we demonstrate by two independent experimental approaches that OA-NO2 binds to the AT1R.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § OA-NO2 forms covalent adducts with the AT1R receptor · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“OA-NO2 significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels.”
- Also stated in: § OA-NO2 specifically inhibits Ang II-induced vasoconstriction · plain
“Thus, OA-NO2 treatment dose-dependently reduced Ang II-dependent vasoconstriction.”
- Also stated in: § Discussion · plain
“In ex vivo vasoconstriction assays, OA-NO2 inhibited Ang II-mediated vascular contractility in an AT1R-dependent fashion.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Also stated in: § OA-NO2 specifically inhibits Ang II-induced vasoconstriction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Systemic delivery of OA and OA-NO2 did not affect baseline systolic or diastolic BP recordings measured by radiotelemetry during the first week of the analysis as compared with polyethylenglycol-treated group that served as vehicle control (Figure 1A and 1C).”
- Also stated in: § OA-NO2 reduces Ang II-induced hypertension · plain
“OA and OA-NO2 (1 mmol/L, infusion rate: 1 μL/min) administered before Ang II delivery (1μmol/L, infusion rate: 1μL/min) did not alter basal BP recordings (Figure 2A and 2B).”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Results > OA-NO2 reduces Ang II-induced hypertension
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § OA-NO2 reduces Ang II-induced hypertension · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We show that systemic administration of OA-NO2 results in a sustained reduction of Ang II-induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion.”
- Also stated in: § OA-NO2 reduces Ang II-induced hypertension · plain
“Under these conditions, OA-NO2 but not OA significantly reduced Ang II-dependent increases in systolic (~15 mmHg reduction) and diastolic BP (~12 mmHg reduction) compared to control OA or vehicle treated animals”
- Also stated in: § Discussion · plain
“Systemic delivery of pharmacological doses of OA-NO2 but not OA resulted in a prolonged and sustained reduction of BP throughout the 14 days of Ang II infusion.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § OA-NO2 reduces Ang II-induced hypertension · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The improved vasoconstriction is specific for the Ang II receptor (AT1R)-mediated signaling since vascular contraction by other G-protein coupled receptors is not altered in response to OA-NO2 treatment.”
- Also stated in: § OA-NO2 specifically inhibits Ang II-induced vasoconstriction · plain
“Interestingly, vasoconstriction elicited by signaling through other members of the G-protein coupled receptor family (GPCR), such as by treatment with phenylephrine (PE) and endothelin-1 (ET-1), was not affected upon OA-NO2 treatment at any concentration given (Figure 3B and 3C and Online Figure IV).”
- Also stated in: § Discussion · plain
“Specificity for the AT1R relies on the observations that OA-NO2 dose-dependently inhibited Ang II-mediated vessel contraction but did not reduced vascular contractility induced by vasoconstrictors signaling through other GPCR, such as the observed endothelin-1 and phenylephrine.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Methods and Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § OA-NO2 specifically inhibits Ang II-induced vasoconstriction · plain
In the paper
“In the context of the vasculature, OA-NO2 inhibits neointimal hyperplasia19 and exerts vasorelaxation of preconstricted aortic rings20.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Introduction
What the sources say
- Not checked yetcites [19] Cole MP Rudolph TK Khoo NK Motanya UN Golin-Bisello F Wertz JW Schopfer FJ Rudolph V Woodcock SR Bolisetty S Ali MS Zhang J Chen YE Agarwal A Freeman BA Bauer PM Nitro-fatty acid inhibition of neointima formation after endoluminal vessel injury Circ Res 2009 105 965 972 19797175 PMC2784279 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“PPARγ activators downregulate AT1R in vascular cells26, 27”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Results > OA-NO2 reduction of Ang II-induced hypertension is a PPARγ independent phenomenon
What the sources say
- Not checked yetcites [26] Takeda K Ichiki T Tokunou T Funakoshi Y Iino N Hirano K Kanaide H Takeshita A Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells Circulation 2000 102 1834 1839 11023940
- Not checked yetcites [27] Sugawara A Takeuchi K Uruno A Ikeda Y Arima S Kudo M Sato K Taniyama Y Ito S Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells Endocrinology 2001 142 3125 3134 11416035
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“These results demonstrate that OA-NO2 diminishes the pressor response to Ang II and inhibits AT1R-dependent vasoconstriction, revealing OA-NO2 as a novel antagonist of Ang II-induced hypertension.”
- Also stated in: § OA-NO2 does not interfere with Ang II binding to the receptor · hedged
“This indicates that OA-NO2 adduction of the AT1R does not affect Ang II binding and represents a novel manner of AT1R antagonism that is distinct from competitive ARBs31.”
- Also stated in: § Discussion · plain
“OA-NO2 antagonizes Ang II signaling due to the formation of stable adducts with the AT1R leading to a reduced vasoconstriction via uncoupling G-protein signaling and subsequently reducing second messenger mobilization.”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Abstract > Conclusions
What the sources say
- Not checked yetcites [31] Vauquelin G Van Liefde I Vanderheyden P Models and methods for studying insurmountable antagonism Trends Pharmacol Sci 2002 23 514 518 12413806
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § OA-NO2 does not interfere with Ang II binding to the receptor · hedged
None of the sources cited for this claim have been checked yet.
In the paper
“certain ARBs inhibit AT1R through PPARγ activity28–30”
§ Nitro-oleic acid inhibits angiotensin II-induced hypertension > Results > OA-NO2 reduction of Ang II-induced hypertension is a PPARγ independent phenomenon
What the sources say
- Not checked yetcites [28] Benson SC Pershadsingh HA Ho CI Chittiboyina A Desai P Pravenec M Qi N Wang J Avery MA Kurtz TW Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity Hypertension 2004 43 993 1002 15007034
- Not checked yetcites [29] Schupp M Janke J Clasen R Unger T Kintscher U Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity Circulation 2004 109 2054 2057 15117841
- Not checked yetcites [30] Imayama I Ichiki T Inanaga K Ohtsubo H Fukuyama K Ono H Hashiguchi Y Sunagawa K Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor gamma Cardiovasc Res 2006 72 184 190 16938288
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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In the citing paper
“NO2-FA display signaling actions that expands both the pharmacokinetics and scope of nitric oxide (·NO) signaling events to include actions beyond the activation of guanylate cyclase-dependent cGMP production [4–7].”
From Nitrite and nitrate-dependent generation of anti-inflammatory fatty acid nitroalkenes (2015) · cites this paper as [4]
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Metadata
- Authors
- Zhang, J., Villacorta, L., Chang, L., Fan, Z., Hamblin, M., Zhu, T., Chen, C. S., Cole, M. P., Schopfer, F. J., Deng, C. X., Garcia-Barrio, M. T., Feng, Y.-H., Freeman, B. A., & Chen, Y. E.
- Affiliations
- Uniformed Services University of the Health Sciences (US)
- From the Cardiovascular Center (J.Z., L.V., L.C., M.H., T.Z., Y.E.C.); and Department of Biomedical Engineering (Z.F., C.X.D.), College of Engineering, University of Michigan; Department of Pharmacology & Chemical Biology (C.S.C., M.P.C., F.J.S., B.A.F.), University of Pittsburgh, Pa; Cardiovascular Research Institute (M.T.G.-B.), Morehouse School of Medicine, Atlanta, Ga; and Department of Pharmacology (Y.-H.F.), Uniformed Services University of the Health Sciences, Bethesda, Md.
- ORCID
- Venue
- Circulation Research
- Published
- 2010-08-20
- Volume
- 107
- Issue
- 4
- Pages
- 540-548
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2937264
- OpenAlex
- W2097005377
- Semantic Scholar
- 1f60e0cb01c7a55c29e7b450dd3191e32d6cffcf
- Cited by
- 121
- References
- 50
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 11 · 2018: 14 · 2017: 7 · 2016: 9 · 2015: 10 · 2014: 10 · 2013: 13 · 2012: 7
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 64937, R01HL064937, HL 58115, R01HL089544, R37HL058115, R01HL058115, HL68878, R01HL088391, R01HL105114, R01HL068878, K99HL095769, R01HL075397, HL089544)
- National Cancer Institute (R01CA116592, CA116592)
- National Institute of Biomedical Imaging and Bioengineering (R01EB008999)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- nitro-oleic acid, angiotensin II, hypertension, angiotensin II type 1 receptor, vasoconstriction, G protein coupling, inositol trisphosphate, calcium mobilization, vascular protection, oleic acid
- MeSH terms
- Angiotensin II, Animals, Blood Pressure, Hypertension, Linoleic Acids, Mice, Inbred C57BL, Nitro Compounds, Oleic Acids, Rats, Sprague-Dawley, Oleic Acid, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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