Abstract 249: Sigma-1 Receptor Agonist Ameliorates Mitochondrial ATP Production and Apoptosis in Cardiac Myocytes

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Hideaki Tagashira ◽  
Norifumi Shioda ◽  
Md. Shenuarin Bhuiyan ◽  
Kohji Fukunaga
Keyword(s):  
Selective Serotonin Reuptake Inhibitors ◽  
Intracellular Localization ◽  
Receptor Expression ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Receptor Stimulation ◽  
Sigma 1 Receptor ◽  
Atp Production ◽  
Sigma 1

Objective: Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction (MI)-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. We previous reported that fluvoxamine with high affinity for sigma-1 receptor ameliorates cardiac hypertrophy and dysfunction via sigma-1 receptor stimulation. In non-cardiomyocytes, sigma-1 receptor interacts with IP 3 receptor (IP 3 R), which may promote Ca 2+ transport to mitochondria. We here investigated the role of sigma-1 receptor for sarcoplasmic reticulum (SR)-mitochondrial Ca 2+ signaling in neonatal rat ventricular cardiomyocytes. Methods: Cultured cardiomyocytes were treated with angiotensin II (Ang II) during 72 hr followed by fluvoxamine and/or NE-100 treatment during the last 24 hr. Then, we investigated intracellular localization of sigma-1 receptor and IP 3 R. We also measured phenylephrine (PE)-induced mitochondrial Ca 2+ and cytosolic Ca 2+ mobilization and ATP content in Ang II-treated cardiomyocytes with or without fluvoxamine treatments. Results: Ang II stimulation for 72 hr elicited cardiomyocyte hypertrophy, downregulation of sigma-1 receptor expression and declined PE-induced Ca 2+ mobilization into cytosol and mitochondria. Fluvoxamine treatments restored sigma-1 receptor expression and PE-induced Ca 2+ mobilization into mitochondria. Moreover, fluvoxamine treatment completely restored Ang II-induced apoptosis. We also confirmed in vivo that fluvoxamine treatment rescue transverse aortic constriction-induced cardiac dysfunction and the reduced ATP concentration. Conclusions: These results suggested that fluvoxamine rescue cardiomyocytes from AngII-induced cardiac myocyte apoptosis through enhancement of SR-mitochondria Ca 2+ transport and mitochondrial ATP production via sigma-1 receptor stimulation.

Abstract 4: The Mitochondrial Ca 2+ Transport and ATP Production Through Sigma-1 Receptor in Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Kohji Fukunaga ◽  
Hideaki Tagashira
Keyword(s):  
Cardiac Dysfunction ◽  
Receptor Agonist ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Sigma 1 Receptor ◽  
Atp Production ◽  
Sigma 1

Objective: Although sigma-1 receptor is originally postulated as an opioid receptor in the central nervous system, we recently defined the higher expression of sigma-1 receptor in cardiac ventricle and kidney as compared to brain tissues (Expert Opin Ther Targets 2010;14:1009-1022). To address the question whether mitochondrial Ca 2+ transport and ATP production in heart are regulated by sigma-1 receptor stimulation, we tested the anti-hypertrophic effects of the specific sigma-1 receptor agonist, SA4503 in transverse aortic constriction (TAC) mice. Methods: We treated mice with SA4503 (0.1, 0.3 and 1.0 mg/kg) orally once a day for 4 weeks after TAC. The cardiac constriction was monitored by echocardiography. The mitochondrial Ca 2+ transport and ATP production with or without SA4503 treatment were measured in cultured neonatal cardiomyocytes. Results: The sigma-1 receptor expression in the left ventricle (LV) decreased significantly over the 4 weeks. SA4503 administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with the recovery of sigma-1 receptor expression in LV. SA4503 also ameliorated the impaired LV fractional shortening. We also investigated the role of sigma-1 receptor for sarcoplasmic reticulum (SR)-mitochondrial Ca 2+ transport in cultured neonatal rat ventricular cardiomyocytes. Exposure to angiotensin II (Ang II) for 72 hr elicited marked cardiomyocyte hypertrophy and declined phenylephrine (PE)-induced Ca 2+ mobilization into cytosol and mitochondria. SA4503 treatment restored significantly the reduced PE-induced Ca 2+ mobilization into mitochondria. Importantly, The Ang II-induced hypertrophy in vitro and transverse aortic constriction-induced cardiac dysfunction in vivo were associated with the reduced ATP concentration, which was completely restored by SA4503 treatment. NE-100, a sigma-1 receptor selective antagonist, abolished these effects induced by SA4503. Conclusion: The specific sigma-1 receptor agonist, SA4503 ameliorates AngII-induced cardiomyocyte hypertrophy and TAC-induced cardiac dysfunction through restoration of SR-mitochondria Ca 2+ transport via sigma-1 receptor stimulation, thereby promoting mitochondrial ATP production.

MicroRNA-297 promotes cardiomyocyte hypertrophy via targeting sigma-1 receptor

Life Sciences ◽  
2017 ◽  
Vol 175 ◽  
pp. 1-10 ◽  
Author(s):  
Qinxue Bao ◽  
Mingyue Zhao ◽  
Li Chen ◽  
Yu Wang ◽  
Siyuan Wu ◽  
...  
Keyword(s):  
Cardiomyocyte Hypertrophy ◽  
Sigma 1 Receptor ◽  
Sigma 1

Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

2006 ◽  
Vol 26 (3) ◽  
pp. 180-191 ◽  
Author(s):  
Shawn D. Hingtgen ◽  
Xin Tian ◽  
Jusan Yang ◽  
Shannon M. Dunlay ◽  
Andrew S. Peek ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Dominant Negative ◽  
Time Dependent ◽  
Neonatal Rat ◽  
Signaling Cascade ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
Akt Activation

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2−·) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2−· production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2−· generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2−· dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2−· generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

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

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.

scholarly journals Sigma-1 Receptor Expression in Sensory Neurons and the Effect of Painful Peripheral Nerve Injury

2013 ◽  
Vol 9 ◽  
pp. 1744-8069-9-47 ◽  
Author(s):  
Madhavi L Bangaru ◽  
Dorothee Weihrauch ◽  
Qing-Bo Tang ◽  
Vasiliki Zoga ◽  
Quinn Hogan ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Peripheral Nerve Injury ◽  
Receptor Expression ◽  
Sigma 1 Receptor ◽  
Sigma 1

Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens

2012 ◽  
Vol 133 (11-12) ◽  
pp. 665-674 ◽  
Author(s):  
Lixin Wang ◽  
Julie A. Eldred ◽  
Peter Sidaway ◽  
Julie Sanderson ◽  
Andrew J.O. Smith ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Er Stress ◽  
Stress Responses ◽  
Human Lens ◽  
Receptor Stimulation ◽  
Sigma 1 Receptor ◽  
Sigma 1
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