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

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.

Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro

2004 ◽  
Vol 286 (3) ◽  
pp. H1063-H1069 ◽  
Author(s):  
Jin-Jiang Pang ◽  
Rong-Kun Xu ◽  
Xiang-Bin Xu ◽  
Ji-Min Cao ◽  
Chao Ni ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Caspase 3 ◽  
Cardiomyocyte Apoptosis ◽  
Protective Effects ◽  
Ang Ii ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Rat Cardiomyocytes ◽  
Induced Apoptosis

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 μmol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 μmol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.

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

2003 ◽  
Vol 284 (4) ◽  
pp. H1269-H1276 ◽  
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.

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

1991 ◽  
Vol 261 (1) ◽  
pp. C77-C85 ◽  
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.

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

2003 ◽  
Vol 81 (2) ◽  
pp. 79-83 ◽  
Author(s):  
Gerd Wallukat ◽  
Dajana Neichel ◽  
Eberhard Nissen ◽  
Volker Homuth ◽  
Friedrich C Luft
Keyword(s):  
Angiotensin Ii ◽  
Neonatal Rat ◽  
Ang Ii ◽  
Extracellular Loop ◽  
Rat Cardiomyocytes ◽  
Clinical Criteria ◽  
Neonatal Rat Cardiomyocytes ◽  
Immuno Globulins ◽  
Igg3 Subclass ◽  
Agonistic Autoantibodies

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.

scholarly journals Role of microRNA-21 in hypertrophic cardiac remodeling

2019 ◽  
Author(s):  
Ken Watanabe ◽  
Taro Narumi ◽  
Tetsu Watanabe ◽  
Yoichiro Otaki ◽  
Tetsuya Takahashi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Specific Inhibitor ◽  
Neonatal Rat ◽  
Major Public Health Problem ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Expression Levels ◽  
Transcriptional Activator Protein ◽  
Tgf Β1

AbstractHypertension is a major public health problem among with aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its impact on hypertrophic cardiac remodeling in hypertension is not known. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively correlated with serum myocardial fibrotic markers. MiR-21 expression levels were significantly upregulated in the mice hearts after angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) compared with control mice. Expression level of programmed cell death 4 (PDCD4), a main target of miR-21, was significantly decreased in Ang II infused mice and TAC mice compared with control mice. Expression levels of transcriptional activator protein 1 (AP-1) and transforming growth factor-β1 (TGF-β1), which were downstream targets of PDCD4, were increased in Ang II infused mice and TAC mice compared with control mice. In vitro, mirVana-miR-21-specific inhibitor attenuated Ang II-induced PDCD4 downregulation and contributed to subsequent deactivation of AP-1/TGF-β1 signaling pathway in neonatal rat cardiomyocytes. Thus, suppression of miR-21 prevents hypertrophic cardiac remodeling by regulating PDCD4, AP-1, and TGF-β1 signaling pathway.

Angiotensin II Induces Nuclear Factor- κ B Activation in Cultured Neonatal Rat Cardiomyocytes Through Protein Kinase C Signaling Pathway

2000 ◽  
Vol 32 (10) ◽  
pp. 1767-1778 ◽  
Author(s):  
Patricia Rouet-Benzineb ◽  
Brigitte Gontero ◽  
Patrick Dreyfus ◽  
Chantal Lafuma
Keyword(s):  
Protein Kinase C ◽  
Angiotensin Ii ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Neonatal Rat ◽  
Nuclear Factor ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes ◽  
Kinase C ◽  
Nuclear Factor Κ B

scholarly journals GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway

2015 ◽  
Vol 55 (3) ◽  
pp. 245-262 ◽  
Author(s):  
Ying Ying ◽  
Huazhang Zhu ◽  
Zhen Liang ◽  
Xiaosong Ma ◽  
Shiwei Li
Keyword(s):  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Specific Inhibitor ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Beta Catenin ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Fatty Acid Transporter ◽  
Induced Apoptosis

Activation of apoptosis in cardiomyocytes by saturated palmitic acids contributes to cardiac dysfunction in diabetic cardiomyopathy. Beta-catenin (b-catenin) is a transcriptional regulator of several genes involved in survival/anti-apoptosis. However, its role in palmitate-induced cardiomyocyte apoptosis remains unclear. Glucagon-like peptide 1 (GLP1) has been shown to exhibit potential cardioprotective properties. This study was designed to evaluate the role of b-catenin signalling in palmitate-induced cardiomyocyte apoptosis and the molecular mechanism underlying the protective effects of GLP1 on palmitate-stressed cardiomyocytes. Exposure of neonatal rat cardiomyocytes to palmitate increased the fatty acid transporter CD36-mediated intracellular lipid accumulation and cardiomyocyte apoptosis, decreased accumulation and nuclear translocation of active b-catenin, and reduced expression of b-catenin target protein survivin and BCL2. These detrimental effects of palmitate were significantly attenuated by GLP1 co-treatment. However, the anti-apoptotic effects of GLP1 were markedly abolished when b-catenin was silenced with a specific short hairpin RNA. Furthermore, analysis of the upstream molecules and mechanisms responsible for GLP1-associated cardiac protection revealed that GLP1 restored the decreased phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3b (GSK3b) in palmitate-stimulated cardiomyocytes. In contrast, inhibition of Akt with an Akt-specific inhibitor MK2206 or blockade of GLP1 receptor (GLP1R) with a competitive antagonist exendin-(9–39) significantly abrogated the GLP1-mediated activation of GSK3b/b-catenin signalling, leading to increased apoptosis in palmitate-stressed cardiomyocytes. Collectively, our results demonstrated for the first time that the attenuated b-catenin signalling may contribute to palmitate-induced cardiomyocyte apoptosis, while GLP1 can protect cardiomyocytes from palmitate-induced apoptosis through activation of GLP1R/Akt/GSK3b-mediated b-catenin signalling.

A novel signaling pathway of ADP-ribosyl cyclase activation by angiotensin II in adult rat cardiomyocytes

2008 ◽  
Vol 295 (1) ◽  
pp. H77-H88 ◽  
Author(s):  
Rukhsana Gul ◽  
Seon-Young Kim ◽  
Kwang-Hyun Park ◽  
Byung-Ju Kim ◽  
Se-Jin Kim ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Signaling Molecules ◽  
Dependent Manner ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Cyclase Activation ◽  
Adp Ribosyl Cyclase ◽  
Sequential Activation

ADP-ribosyl cyclase (ADPR-cyclase) produces a Ca2+-mobilizing second messenger, cADP-ribose (cADPR), from NAD+. In this study, we investigated the molecular basis of ADPR-cyclase activation in the ANG II signaling pathway and cellular responses in adult rat cardiomyocytes. The results showed that ANG II generated biphasic intracellular Ca2+ concentration increases that include a rapid transient Ca2+ elevation via inositol trisphosphate (IP3) receptor and sustained Ca2+ rise via the activation of L-type Ca2+ channel and opening of ryanodine receptor. ANG II-induced sustained Ca2+ rise was blocked by a cADPR antagonistic analog, 8-bromo-cADPR, indicating that sustained Ca2+ rise is mediated by cADPR. Supporting the notion, ADPR-cyclase activity and cADPR production by ANG II were increased in a time-dependent manner. Application of pharmacological inhibitors and immunological analyses revealed that cADPR formation was activated by sequential activation of Src, phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), phospholipase C (PLC)-γ1, and IP3-mediated Ca2+ signal. Inhibitors of these signaling molecules not only completely abolished the ANG II-induced Ca2+ signals but also inhibited cADPR formation. Application of the cADPR antagonist and inhibitors of upstream signaling molecules of ADPR-cyclase inhibited ANG II-stimulated hypertrophic responses, which include nuclear translocation of Ca2+/calcineurin-dependent nuclear factor of activated T cells 3, protein expression of transforming growth factor-β1, and incorporation of [3H]leucine in cardiomyocytes. Taken together, these findings suggest that activation of ADPR-cyclase by ANG II entails a novel signaling pathway involving sequential activation of Src, PI 3-kinase/Akt, and PLC-γ1/IP3 and that the activation of ADPR-cyclase can lead to cardiac hypertrophy.

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

2008 ◽  
Vol 72 (8) ◽  
pp. 1346-1350 ◽  
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

Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium Against Ischemia-Reperfusion Injury in Canis

Hypertension ◽  
2021 ◽  
Vol 78 (5) ◽  
pp. 1541-1554
Author(s):  
Hongyun Wang ◽  
Rusitanmujiang Maimaitiaili ◽  
Jianhua Yao ◽  
Yuling Xie ◽  
Sujing Qiang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Embryonic Stem ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes

Plasma circulating extracellular vesicles (EVs) have been utilized as a potential therapeutic strategy to treat ischemic disease through intramyocardial injection (efficient but invasive) or tail vein injection (noninvasive but low cardiac retention). An effective and noninvasive delivery of EVs for future clinical use is necessary. The large animal (canine) model was complemented with a murine ischemia-reperfusion injury (IRI) model, as well as H9 human embryonic stem cell–induced cardiomyocytes or neonatal rat cardiomyocytes to investigate the effective delivery method and the role of plasma EVs in the IRI model. We further determine the crucial molecule within EVs that confers the cardioprotective role in vivo and in vitro and investigate the efficiency of CHP (cardiac homing peptide)-linked EVs in alleviating IRI. D-SPECT imaging showed that percutaneous intracoronary delivery of EVs reduced infarct extent in dogs. CHP-EVs further reduced IRI-induced cardiomyocyte apoptosis in mice and neonatal rat cardiomyocytes. Mechanistically, administration of EVs by percutaneous intracoronary delivery (in dog) and myocardial injection (in mice) just before reperfusion reduced infarct size of IRI by increasing miR-486 levels. miR-486–deleted EVs exacerbated oxygen-glucose deprivation/reoxygenation–induced human embryonic stem cell–induced cardiomyocytes and neonatal rat cardiomyocyte apoptosis. EV-miR-486 inhibited the PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression and then promoted AKT (protein kinase B) activation in human embryonic stem cell–induced cardiomyocytes and neonatal rat cardiomyocytes. In conclusion, plasma-derived EVs convey miR-486 to the myocardium and attenuated IRI-induced infarction and cardiomyocyte apoptosis. CHP strategy was effective to improve cardiac retention of EVs in mice (in vivo) and dogs (ex vivo).

Sign in / Sign up

Export Citation Format

Share Document