Agonistic autoantibodies directed against the angiotensin II AT1 receptor in patients with preeclampsia

We showed that sera from patients with preeclampsia contain autoantibodies directed against the angiotensin II AT1 receptor. The antibodies recognize an epitope on the second extracellular loop of the receptor and are immuno globulins of the IgG3 subclass. The antibodies accelerate the beating rate of neonatal rat cardiomyocytes. The agonistic effect can be blocked with the AT1 receptor blocker losartan and can be neutralized by a peptide corresponding to the AT1 receptor's second extracellular loop. In further studies we shown that the autoantibodies recognize a specific conformation of the AT1 receptor. Cleavage of the external disulfide bond with dithiothreitol caused an inactivation of the receptor when stimulated either with Ang II or the autoantibodies in a system of cultured neonatal rat cardiomyocytes. Long-term stimulation of the AT1 receptor with either agonists down-regulated the AT1 receptor-mediated response to a second Ang II stimulation. These observations show that the agonistic autoantibodies behave pharmacologically in a similar fashion to Ang II. We have found the autoantibodies in all women meeting the clinical criteria of preeclampsia and suggest that they may be important to the pathogenesis of the disease.Key words: angiotensin II, preeclampsia, autoantibodies, IgG subclasses, dithiotrietol, AT1 receptor.

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Cysteinyl leukotriene-dependent [Ca2+]iresponses to angiotensin II in cardiomyocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00303.2002 ◽

2003 ◽

Vol 284 (4) ◽

pp. H1269-H1276 ◽

Cited By ~ 6

Author(s):

Pinggang Liu ◽

Derek A. Misurski ◽

Venkat Gopalakrishnan

Keyword(s):

Angiotensin Ii ◽

Single Cells ◽

Receptor Activation ◽

Neonatal Rat ◽

Ang Ii ◽

Rat Cardiomyocytes ◽

Endothelin 1 ◽

Neonatal Rat Cardiomyocytes ◽

Cysteinyl Leukotriene

With the use of fura 2 measurements in multiple and single cells, we examined whether cysteinyl leukotrienes (CysLT) mediate angiotensin II (ANG II)-evoked increases in cytosolic free Ca2+ concentration ([Ca2+]i) in neonatal rat cardiomyocytes. ANG II-evoked CysLT release peaked at 1 min. The angiotensin type 1 (AT1) antagonist losartan, but not the AT2antagonist PD-123319, attenuated the elevations in [Ca2+]i and CysLT levels evoked by ANG II. Vasopressin and endothelin-1 increased [Ca2+]i but not CysLT levels. The 5-lipoxygenase (5-LO) inhibitor AA-861 and the CysLT1-selective antagonist MK-571 reduced the maximal [Ca2+]i responses to ANG II but not to vasopressin and endothelin-1. While MK-571 reduced the responses to leukotriene D4 (LTD4), the dual CysLT antagonist BAY-u9773 completely blocked the [Ca2+]i elevation to both LTD4and LTC4. These data confirm that ANG II-evoked increases, but not vasopressin- and endothelin-1-evoked increases, in [Ca2+]i involve generation of the 5-lipoxygenase metabolite CysLT. The inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] antagonist 2-aminoethoxydiphenyl borate attenuated the [Ca2+]i responses to ANG II and LTD4. Thus AT1 receptor activation by ANG II is linked to CysLT-mediated Ca2+ release from Ins(1,4,5)P3-sensitive intracellular stores to augment direct ANG II-evoked Ca2+ mobilization in rat cardiomyocytes.

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Aldosterone, but Not Angiotensin II, Reduces Angiotensin Converting Enzyme 2 Gene Expression Levels in Cultured Neonatal Rat Cardiomyocytes

Circulation Journal ◽

10.1253/circj.72.1346 ◽

2008 ◽

Vol 72 (8) ◽

pp. 1346-1350 ◽

Cited By ~ 28

Author(s):

Megumi Yamamuro ◽

Michihiro Yoshimura ◽

Masafumi Nakayama ◽

Koji Abe ◽

Hitoshi Sumida ◽

...

Keyword(s):

Gene Expression ◽

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Neonatal Rat ◽

Converting Enzyme ◽

Rat Cardiomyocytes ◽

Angiotensin Converting Enzyme 2 ◽

Expression Levels ◽

Neonatal Rat Cardiomyocytes ◽

Gene Expression Levels

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Effect of angiotensin II on cytosolic free calcium in neonatal rat cardiomyocytes

AJP Cell Physiology ◽

10.1152/ajpcell.1991.261.1.c77 ◽

1991 ◽

Vol 261 (1) ◽

pp. C77-C85 ◽

Cited By ~ 69

Author(s):

D. C. Kem ◽

E. I. Johnson ◽

A. M. Capponi ◽

D. Chardonnens ◽

U. Lang ◽

...

Keyword(s):

Angiotensin Ii ◽

Sarcoplasmic Reticulum ◽

Ventricular Myocytes ◽

Acute Effect ◽

Neonatal Rat ◽

Free Calcium ◽

Receptor Subtype ◽

Ang Ii ◽

Rat Cardiomyocytes ◽

Neonatal Rat Ventricular Myocytes

The effect of angiotensin II (ANG II) on cytosolic free Ca2+ concentration ([Ca2+]i) was studied in cultured neonatal rat ventricular myocytes. [Ca2+]i was estimated in groups of one to three cells by dual-wavelength microfluorometry or in cell populations using conventional fluorometry. ANG II (10(-8) M) produced an acute short-lived increase over the control basal diastolic [Ca2+]i and increased the frequency of the [Ca2+]i transients. The amplitude of the [Ca2+]i transients was decreased to 64.4% of basal values. The effect of ANG II on [Ca2+]i was blocked by the selective AT1 receptor subtype antagonist Du Pont 753 but not by the AT2 antagonist PD 123319. Removal of extracellular Ca2+ or blockade of voltage-gated Ca2+ channels in cells cultured for 5-7 days abolished the [Ca2+]i transients, but only partially diminished the effect of ANG II on [Ca2+]i. Thapsigargin, an inhibitor of sarcoplasmic reticulum Ca(2+)-Mg(2+)-ATPase, reduced or abolished the [Ca2+]i response to ANG II. Phorbol 12-myristate 13-acetate (PMA), 10(-6) and 10(-7) M, also decreased the amplitude of the Ca2+ transients similar to ANG II. Pretreatment with 10(-6) M PMA or 10(-6) M 1-oleoyl-2-acetyl-glycerol (OAG) inhibited the initial rise in [Ca2+]i and the Ca2+ transients. Thus ANG II produces an acute rise in [Ca2+]i which is derived predominantly from sarcoplasmic reticulum intracellular stores. This acute effect is followed by a significant reduction in the amplitude for the Ca2+ transient and may be mediated by activation of protein kinase C.

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Abstract 72: Hydrogen Sulfide Prevents Myocardial Hypertrophy in a Klf5-dependent Manner

Circulation Research ◽

10.1161/res.117.suppl_1.72 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Guoliang Meng ◽

Liping Xie ◽

Yong Ji

Keyword(s):

Oxidative Stress ◽

Hydrogen Sulfide ◽

Promoter Activity ◽

Myocardial Hypertrophy ◽

Neonatal Rat ◽

Cardiomyocyte Hypertrophy ◽

Dependent Manner ◽

Ang Ii ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes

Rationale: H 2 S is a gasotransmitter that regulates multiple cardiovascular functions. Krüppel-like transcription factor (KLF) exerts diverse functions in the cardiovascular system. Objectives: The aim of present study was to investigate the effect of hydrogen sulfide (H 2 S) on myocardial hypertrophy. Methods and results: Myocardial samples of 22 patients with left ventricle hypertrophy were collected and underwent histological and molecular biological analysis. Spontaneously hypertensive rats (SHR) and neonatal rat cardiomyocytes were studied for functional and signaling response to GYY4137, a H 2 S-releasing compound. Expression of cystathionine -lyase (CSE), a main enzyme for H 2 S generation in human heart, decreased in human hypertrophic myocardium, while KLF5 expression increased. In SHR treated with GYY4137 for 4 weeks, myocardial hypertrophy was inhibited as evidenced by improvement in cardiac structural parameters, heart mass index, size of cardiac myocytes and expression of atrial natriuretic peptide (ANP). Levels of oxidative stress and phosphorylation of mitogen-activated protein kinases were also decreased after H 2 S treatment. H 2 S diminished expression of the KLF5 in myocardium of SHR and in neonatal rat cardiomyocytes rendered hypertrophy by angiotensin II (Ang II). H 2 S also inhibited ANP promoter activity and ANP expression in Ang II-induced neonatal rat cardiomyocyte hypertrophy, and these effects were suppressed by KLF5 knockdown. KLF5 promoter activity was increased by Ang II stimulation, and this was reversed by H 2 S. H 2 S also decreased activity of specificity protein-1 (SP-1) binding to the KLF5 promoter and attenuated KLF5 nuclear translocation by Ang II stimulation. Conclusion: H 2 S attenuated myocardial hypertrophy, which might be related to inhibiting oxidative stress and decreasing ANP transcription activity in a KLF5-dependent manner.

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Mitogen-activated protein kinases ERK 1/2- and p38-GATA4 pathways mediate the Ang II-induced activation of FGF2 gene in neonatal rat cardiomyocytes

Biochemical Pharmacology ◽

10.1016/j.bcp.2010.11.012 ◽

2011 ◽

Vol 81 (4) ◽

pp. 518-525 ◽

Cited By ~ 5

Author(s):

Wenjie Tang ◽

Youzhen Wei ◽

Kang Le ◽

Zhi Li ◽

Yingxia Bao ◽

...

Keyword(s):

Protein Kinases ◽

Neonatal Rat ◽

Ang Ii ◽

Rat Cardiomyocytes ◽

Mitogen Activated Protein Kinases ◽

Neonatal Rat Cardiomyocytes ◽

Mitogen Activated Protein

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Telmisartan, an angiotensin II type 1 receptor antagonist, attenuates T-type Ca2+ channel expression in neonatal rat cardiomyocytes

European Journal of Pharmacology ◽

10.1016/j.ejphar.2009.03.024 ◽

2009 ◽

Vol 609 (1-3) ◽

pp. 105-112 ◽

Cited By ~ 22

Author(s):

Masaki Morishima ◽

Yan Wang ◽

Yuko Akiyoshi ◽

Shinji Miyamoto ◽

Katsushige Ono

Keyword(s):

Angiotensin Ii ◽

Receptor Antagonist ◽

Neonatal Rat ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes ◽

Channel Expression

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Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II-Induced Cardiomyocyte Apoptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9979706 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Man Xu ◽

Xue-Yuan Bi ◽

Xiao-Rong Xue ◽

Xing-Zhu Lu ◽

Qiong-Ge Li ◽

...

Keyword(s):

Angiotensin Ii ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Cardiomyocyte Apoptosis ◽

Neonatal Rat ◽

In Vivo Studies ◽

Terminal Deoxynucleotidyl Transferase ◽

Ang Ii ◽

Rat Cardiomyocytes ◽

Apoptosis Pathway

Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10−6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

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