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.

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.

scholarly journals Celastrol Attenuates Angiotensin II–Induced Cardiac Remodeling by Targeting STAT3

2020 ◽  
Vol 126 (8) ◽  
pp. 1007-1023 ◽  
Author(s):  
Shiju Ye ◽  
Wu Luo ◽  
Zia A. Khan ◽  
Gaojun Wu ◽  
Lina Xuan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Nuclear Translocation ◽  
Heart Function ◽  
Ang Ii ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

Rationale: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. Objective: We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction. Methods and Results: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy. Conclusions: Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.

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

scholarly journals Cardioprotective Effect of the Selective Sigma-1 Receptor Agonist, SA4503

2014 ◽  
Vol 134 (6) ◽  
pp. 707-713 ◽  
Author(s):  
Kohga Hirano ◽  
Hideaki Tagashira ◽  
Kohji Fukunaga
Keyword(s):  
Receptor Agonist ◽  
Cardioprotective Effect ◽  
Sigma 1 Receptor ◽  
Sigma 1

scholarly journals Aerobic Exercise Attenuates Pressure Overload-Induced Cardiac Dysfunction through Promoting Skeletal Muscle Microcirculation and Increasing Muscle Mass

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Ling-Yan Yuan ◽  
Pei-Zhao Du ◽  
Min-Min Wei ◽  
Qi Zhang ◽  
Le Lu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Function ◽  
Aerobic Exercise ◽  
Muscle Mass ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Protein Levels ◽  
Skeletal Muscle Microcirculation

Background. Aerobic exercise has been proven to have a positive effect on cardiac function after hypertension; however, the mechanism is not entirely clarified. Skeletal muscle mass and microcirculation are closely associated with blood pressure and cardiac function. Objective. This study was designed to investigate the effects of aerobic exercise on the skeletal muscle capillary and muscle mass, to explore the possible mechanisms involved in exercise-induced mitigation of cardiac dysfunction in pressure overload mice. Methods. In this study, 60 BALB/C mice aged 8 weeks were randomly divided into 3 groups: control (CON), TAC, and TAC plus exercise (TAE) group and utilized transverse aortic constriction (TAC) to establish hypertensive model; meanwhile, treadmill training is used for aerobic exercise. After 5 days of recovery, mice in the TAE group were subjected to 10-week aerobic exercise. Carotid pressure and cardiac function were examined before mice were executed by Millar catheter and ultrasound, respectively. Muscle mass of gastrocnemius was weighed; cross-sectional area and the number of capillaries of gastrocnemius were detected by HE and immunohistochemistry, respectively. The mRNA and protein levels of VEGF in skeletal muscle were determined by RT-PCR and western blot, respectively. Results. We found that ① 10-week aerobic exercise counteracted hypertension and attenuated cardiac dysfunction in TAC-induced hypertensive mice; ② TAC decreased muscle mass of gastrocnemius and resulted in muscle atrophy, while 10-week aerobic exercise could reserve transverse aortic constriction-induced the decline of muscle mass and muscle atrophy; and ③ TAC reduced the number of capillaries and the protein level of VEGF in gastrocnemius, whereas 10-week aerobic exercise augmented the number of capillaries, the mRNA and protein levels of VEGF in mice were subjected to TAC surgery. Conclusions. This study indicates that 10-week aerobic exercise might fulfill its blood pressure-lowering effect via improving skeletal muscle microcirculation and increasing muscle mass.

Sigma-1 receptor agonist fluvoxamine for delirium in older adults

2011 ◽  
Vol 27 (9) ◽  
pp. 981-983 ◽  
Author(s):  
Kenji Hashimoto ◽  
Tsutomu Furuse
Keyword(s):  
Older Adults ◽  
Receptor Agonist ◽  
Sigma 1 Receptor ◽  
Sigma 1

scholarly journals Modeling heart failure risk in diabetes and kidney disease: limitations and potential applications of transverse aortic constriction in high-fat-fed mice

2018 ◽  
Vol 314 (6) ◽  
pp. R858-R869 ◽  
Author(s):  
Wei Sheng Tan ◽  
Thomas P. Mullins ◽  
Melanie Flint ◽  
Sarah L. Walton ◽  
Helle Bielefeldt-Ohmann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Kidney Disease ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Transverse Aortic Constriction ◽  
High Fat ◽  
Aortic Constriction ◽  
Failure Risk ◽  
Cardiovascular Prognosis ◽  
Fat Feeding

There is an increased incidence of heart failure in individuals with diabetes mellitus (DM). The coexistence of kidney disease in DM exacerbates the cardiovascular prognosis. Researchers have attempted to combine the critical features of heart failure, using transverse aortic constriction, with DM in mice, but variable findings have been reported. Furthermore, kidney outcomes have not been assessed in this setting; thus its utility as a model of heart failure in DM and kidney disease is unknown. We generated a mouse model of obesity, hyperglycemia, and mild kidney pathology by feeding male C57BL/6J mice a high-fat diet (HFD). Cardiac pressure overload was surgically induced using transverse aortic constriction (TAC). Normal diet (ND) and sham controls were included. Heart failure risk factors were evident at 8-wk post-TAC, including increased left ventricular mass (+49% in ND and +35% in HFD), cardiomyocyte hypertrophy (+40% in ND and +28% in HFD), and interstitial and perivascular fibrosis (Masson’s trichrome and picrosirius red positivity). High-fat feeding did not exacerbate the TAC-induced cardiac outcomes. At 11 wk post-TAC in a separate mouse cohort, echocardiography revealed reduced left ventricular size and increased left ventricular wall thickness, the latter being evident in ND mice only. Systolic function was preserved in the TAC mice and was similar between ND and HFD. Thus combined high-fat feeding and TAC in mice did not model the increased incidence of heart failure in DM patients. This model, however, may mimic the better cardiovascular prognosis seen in overweight and obese heart failure patients.

AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer's disease

2017 ◽  
Vol 14 (6) ◽  
pp. 811-823 ◽  
Author(s):  
Hélène Hall ◽  
Maria Florencia Iulita ◽  
Palma Gubert ◽  
Lisi Flores Aguilar ◽  
Adriana Ducatenzeiler ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Receptor Agonist ◽  
Transgenic Rat ◽  
Sigma 1 Receptor ◽  
Model Of Alzheimer’S Disease ◽  
Sigma 1 ◽  
Disease Modifying ◽  
Transgenic Rat Model
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