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  • 1
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    In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hypertension Vol. 78, No. 1 ( 2021-07), p. 128-137
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 78, No. 1 ( 2021-07), p. 128-137
    Abstract: Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold; P 〈 0.0001) and MasR (Mas oncoreceptor; 2–3-fold, P 〈 0.05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.121.17164
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2094210-2
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  • 2
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    Abstract 12273: Crispr-Mutation of the Na + -k + Pump β1-Subunit Protects Against Cardiac Fibrosis and Heart Failure in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Introduction: The Na+-K+ pump controls translocation of Na+ and K+ across the cell membrane which indirectly affects heart muscle contraction. Glutathionylation of the Na+-K+ pump’s β1 subunit (NKβ1) is a reversible post-translational oxidative modification, where a glutathione adduct forms a disulphide bond with the cysteine residue at site 45, leading to a reduction in pump activity. Using CRISPR/Cas9 technology, we created a transgenic mouse line (CRISPR-β1) that has a mutation in cysteine to serine at site 45 on NKβ1, causing insensitivity to β1-GSS. Hypothesis: We hypothesize that a mutation of the β1-GSS can inhibit transverse aortic constriction (TAC)-induced cardiac fibrosis. Methods and Results: TAC was induced in both the wild-type (WT) and CRISPR-NKβ1 mutated mice (CRISPR-β1) over a period of four weeks. Gene sequencing showed that cysteine 45 was replaced by serine, and immunoprecipitation of the free cysteine demonstrated that cysteine 45 was mutated in the β1 subunit of the CRISPR-β1 mice hearts. TAC significantly reduced cardiac function in the WT but not the CRISPR-β1 mice (ejection fraction: WT TAC: 36.24% ± 3.49%; CRISPR-β1 TAC: 57.5% ± 3.41%). Similarly, we found that the CRISPR-β1 mice were protected from cardiac hypertrophy, as evidenced by a significant reduction in cardiomyocytes size (WT TAC: 452.1 μm2 ± 30.74 μm2 ; CRISPR-β1 TAC: 271.1 μm 2 ± 11.0 μm 2 ). TAC significantly increased interstitial and perivascular fibrosis in the left ventricles of WT but not the CRISPR-β1 mice (interstitial: WT TAC: 18.4% ± 1.96%; CRISPR-β1 TAC: 5.2% ± 1.62%, perivascular: WT TAC: 42.6% ± 4.5%; CRISPR-β1 TAC: 22.01% ± 1.6%). Cardioprotective effects observed in the CRISPR-β1 mice were at least in part attributed to a significant reduction in the expression of ANP, BNP, Tgfb1, Fn1 and Ctgf genes. Conclusions: Our data indicate that CRISPR mutation of the Na+-K+ pump’s β1 subunit prevents the development of cardiac fibrosis and heart failure in a TAC-induced mouse model.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.12273
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 3
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    Abstract 043: Targeting the Angiotensin Type 2 Receptor With Relaxin Confers Protection Against Renal Fibrosis and Vascular Dysfunction in Female Stroke Prone-Spontaneously Hypertensive Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Hypertension Vol. 72, No. Suppl_1 ( 2018-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 72, No. Suppl_1 ( 2018-09)
    Abstract: The angiotensin type 2 receptor (AT 2 R) mediates cardiovascular and renal protection in females of reproductive age, a mechanism that is lost with advancing age. Recently, we demonstrated that the nitric oxide-promoting and transforming growth factor-β1 inhibitory actions of relaxin (RLX) involve an interaction between the relaxin-insulin like family peptide receptor 1 (RXFP1) and the AT 2 R. In the present study, we aimed to determine whether RLX induces cardio-renal protection and slows the progression of end-organ damage, via an AT 2 R-dependent mechanism. In female stroke prone-spontaneously hypertensive rats (SP-SHR) at 6 (young) and 14-15 (aged reproductively senescent) months of age arterial pressure, cardiac function, glomerular filtration rate (GFR) and proteinuria were measured before and after 4 weeks of treatment with vehicle (sodium acetate s.c.), RLX (serelaxin; 0.5mg/kg/day s.c.) or RLX+PD123319 (AT 2 R antagonist; 3mg/kg/day s.c). In addition, aortic endothelium-dependent relaxation in response to acetylcholine was assessed and cardiac and renal tissues were histologically analyzed for fibrosis. An age-related decline in GFR and increases in arterial pressure, proteinuria and cardiac and renal fibrosis were observed (all P 〈 0.05; n=4-8). RLX treatment had no significant effect on these variables in the aged group. However, in aged animals, RLX markedly improved endothelial function (~30% increase in maximal vasodilation as compared to vehicle counterparts, P=0.0002; n=4-6). This effect was partially reversed by co-infusion with PD123319, relative to RLX alone (~14% reduced maximal vasodilation, P=0.03; n=6). In young females, RLX+PD123319 as compared to RLX treatment alone, exacerbated glomerular (11.6±1.2% vs 8.5±0.7%, respectively, P=0.04) and tubulointerstitial (3.3±0.2% vs 1.6±0.2%, respectively, P=0.0002) fibrosis. In conclusion, the cardio-renal protective actions of relaxin are dependent in part, upon an interaction with the AT 2 R. Thus, targeting the RXFP1-AT 2 R axis may be a therapeutic option for the treatment of cardiovascular disease and associated end-organ damage in hypertensive women.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.72.suppl_1.043
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2094210-2
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  • 4
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    Abstract 045: The Enhanced Pressor Response to AngII in Aged Females is Attenuated by Estrogen Replacement via an AT 2 R-mediated Mechanism
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Hypertension Vol. 70, No. suppl_1 ( 2017-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. suppl_1 ( 2017-09)
    Abstract: Loss of estrogen (E 2 ) following menopause contributes to the sharp rise in cardiovascular risk with age. E 2 is postulated to play a protective role against hypertension and end-organ damage by counterbalancing the pressor actions of the RAS and enhancing the depressor RAS pathways. The aim was to determine whether E 2 replacement in aged females can lower arterial pressure and improve endothelial function via an AT 2 R-mediated mechanism. MAP was measured via telemetry in ovary-intact adult (4-month old), aged (17-month old) and aged+E 2 (3 μg/day sc) FVB/N female mice, which were co-treated with vehicle, AngII (600 ng/kg/min sc) or AngII+PD (PD123319, AT 2 R antagonist; 3 mg/kg/day sc). On day 21 of treatment, endothelium-dependent relaxation in response to acetylcholine was assessed in aortic vessels. Cardiac and renal, tissue fibrosis and gene expression of E 2 receptors and RAS components were also analysed. Basal MAP was lower in E 2 -treated aged mice (90±1 mmHg, n=20) relative to adult (94±1 mmHg, n=10) and aged controls (94±1 mmHg; n=21, both P 〈 0.05). Similar to previous studies, the AngII pressor response was enhanced in aged compared to adult females (Figure). E 2 treatment reduced the AngII pressor response in aged females (Figure). Moreover, the attenuated pressor response observed in the aged E 2 +AngII group was abolished by co-infusion with PD (Figure). Endothelial function was markedly impaired with age (~23% reduced maximal vasodilation, P=0.03) and worsened by AngII infusion (~38%, P=0.001), however E 2 did not significantly improve the response in any group. In conclusion, E 2 replacement may reinstate cardio-protection in aged females via an AT 2 R-mediated mechanism.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.70.suppl_1.045
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2094210-2
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  • 5
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    Absence of renal hypoxia in the subacute phase of severe renal ischemia-reperfusion injury
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Renal Physiology Vol. 315, No. 5 ( 2018-11-01), p. F1358-F1369
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 315, No. 5 ( 2018-11-01), p. F1358-F1369
    Abstract: Tissue hypoxia has been proposed as an important event in renal ischemia-reperfusion injury (IRI), particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats. We hypothesized that the kidney is hypoxic 24 h and 5 days after an hour of bilateral renal ischemia, driven by a disturbed balance between renal oxygen delivery (Do 2 ) and oxygen consumption (V̇o 2 ). Renal Do 2 was not significantly reduced in the subacute phase of IRI. In contrast, renal V̇o 2 was 55% less 24 h after reperfusion and 49% less 5 days after reperfusion than after sham ischemia. Inner medullary tissue Po 2 , measured by radiotelemetry, was 25 ± 12% (mean ± SE) greater 24 h after ischemia than after sham ischemia. By 5 days after reperfusion, tissue Po 2 was similar to that in rats subjected to sham ischemia. Tissue Po 2 measured by Clark electrode was consistently greater 24 h, but not 5 days, after ischemia than after sham ischemia. Cellular hypoxia, assessed by pimonidazole adduct immunohistochemistry, was largely absent at both time points, and tissue levels of hypoxia-inducible factors were downregulated following renal ischemia. Thus, in this model of severe IRI, tissue hypoxia does not appear to be an obligatory event during the subacute phase, likely because of the markedly reduced oxygen consumption.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00249.2018
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477287-5
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  • 6
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    AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Journal of the American Society of Nephrology Vol. 30, No. 11 ( 2019-11), p. 2191-2207
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 11 ( 2019-11), p. 2191-2207
    Abstract: Studies have shown that the hormone serelaxin, which has organ-protective actions mediated via relaxin family peptide receptor 1 (RXFP1), its cognate G protein–coupled receptor, requires the angiotensin II type 2 receptor (AT 2 R) to ameliorate renal fibrogenesis in vitro and in vivo . In this study, the authors describe a functional interaction between RXFP1, AT 2 R, and the angiotensin II type 1 receptor (AT 1 R), all of which are expressed on extracellular matrix–producing myofibroblasts, the cellular basis of progressive fibrosis. The crosstalk between these G protein–coupled receptors allows antagonists acting at each receptor to directly or allosterically block the antifibrotic actions of agonists acting at AT 2 R or RXFP1. These findings have significant therapeutic implications for a mechanistic understanding of the concomitant use of drugs acting at each receptor. Background Recombinant human relaxin-2 (serelaxin), which has organ-protective actions mediated via its cognate G protein–coupled receptor relaxin family peptide receptor 1 (RXFP1), has emerged as a potential agent to treat fibrosis. Studies have shown that serelaxin requires the angiotensin II (AngII) type 2 receptor (AT 2 R) to ameliorate renal fibrogenesis in vitro and in vivo . Whether its antifibrotic actions are affected by modulation of the AngII type 1 receptor (AT 1 R), which is expressed on myofibroblasts along with RXFP1 and AT 2 R, is unknown. Methods We examined the signal transduction mechanisms of serelaxin when applied to primary rat renal and human cardiac myofibroblasts in vitro , and in three models of renal- or cardiomyopathy-induced fibrosis in vivo . Results The AT 1 R blockers irbesartan and candesartan abrogated antifibrotic signal transduction of serelaxin via RXFP1 in vitro and in vivo . Candesartan also ameliorated serelaxin’s antifibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that candesartan’s inhibitory effects were not confined to the kidney. We also demonstrated in a transfected cell system that serelaxin did not directly bind to AT 1 Rs but that constitutive AT 1 R–RXFP1 interactions could form. To potentially explain these findings, we also demonstrated that renal and cardiac myofibroblasts expressed all three receptors and that antagonists acting at each receptor directly or allosterically blocked the antifibrotic effects of either serelaxin or an AT 2 R agonist (compound 21). Conclusions These findings have significant implications for the concomitant use of RXFP1 or AT 2 R agonists with AT 1 R blockers, and suggest that functional interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2019060597
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2029124-3
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  • 7
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    Online Resource
    Sex- and age-related differences in arterial pressure and albuminuria in mice
    Springer Science and Business Media LLC ; 2016
    In:  Biology of Sex Differences Vol. 7, No. 1 ( 2016-12)
    Details
    In: Biology of Sex Differences, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2016-12)
    Type of Medium: Online Resource
    ISSN: 2042-6410
    URL: Article
    DOI: 10.1186/s13293-016-0110-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2587352-0
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  • 8
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    Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors
    Elsevier BV ; 2023
    In:  Journal of the American College of Cardiology Vol. 82, No. 13 ( 2023-09), p. 1343-1359
    Details
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 82, No. 13 ( 2023-09), p. 1343-1359
    Type of Medium: Online Resource
    ISSN: 0735-1097
    URL: Article
    DOI: 10.1016/j.jacc.2023.06.045
    RVK:
    XA 17760
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1468327-1
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  • 9
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    Relaxin Attenuates Organ Fibrosis via an Angiotensin Type 2 Receptor Mechanism in Aged Hypertensive Female Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Kidney360 Vol. 2, No. 11 ( 2021-11), p. 1781-1792
    Details
    In: Kidney360, Ovid Technologies (Wolters Kluwer Health), Vol. 2, No. 11 ( 2021-11), p. 1781-1792
    Abstract: Relaxin attenuates tissue fibrosis in an organ- and age-specific manner. The antifibrotic actions of relaxin are mediated via an angiotensin type 2 receptor mechanism. Relaxin replacement therapy is a potential antifibrotic for cardiovascular and kidney disease in postmenopausal women. Background The antifibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT 2 R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via AT 2 R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection via an AT 2 R-dependent mechanism in adult and aged female stroke-prone spontaneously hypertensive rats (SHRSPs). Methods In 6-month-old (6MO) and 15-month-old ([15MO]; reproductively senescent) female SHRSP, systolic BP (SBP), GFR, and proteinuria were measured before and after 4 weeks of treatment with vehicle (Veh), RLX (0.5 mg/kg per day s.c.), or RLX+PD123319 (AT 2 R antagonist; 3 mg/kg per day s.c.). Aortic endothelium–dependent relaxation and fibrosis of the kidney, heart, and aorta were assessed. Results In 6MO SHRSP, RLX significantly enhanced GFR by approximately 25% ( P =0.001) and reduced cardiac fibrosis ( P =0.01) as compared with vehicle-treated counterparts. These effects were abolished or blunted by PD123319 coadministration. In 15MO females, RLX reduced interstitial renal ( P =0.02) and aortic ( P =0.003) fibrosis and lowered SBP (13±3 mm Hg; P =0.04) relative to controls. These effects were also blocked by PD123319 cotreatment (all P =0.05 versus RLX treatment alone). RLX also markedly improved vascular function by approximately 40% ( P 〈 0.001) in 15MO SHRSP, but this was not modulated by PD123319 cotreatment. Conclusions The antifibrotic and organ-protective effects of RLX, when administered to a severe model of hypertension, conferred cardiorenal protection in adult and reproductively senescent female rats to a great extent via an AT 2 R-mediated mechanism.
    Type of Medium: Online Resource
    ISSN: 2641-7650
    URL: Article
    DOI: 10.34067/KID.0002722021
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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