scholarly journals Cardiac‐Specific Deletion of Orai3 Leads to Severe Dilated Cardiomyopathy and Heart Failure in Mice

2021 ◽  
Author(s):  
Jesse Gammons ◽  
Mohamed Trebak ◽  
Salvatore Mancarella
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Transient Receptor Potential ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Adult Mice ◽  
Cardiac Phenotype ◽  
Transient Receptor

Background Orai3 is a mammalian‐specific member of the Orai family (Orai1‒3) and a component of the store‐operated Ca 2+ entry channels. There is little understanding of the role of Orai channels in cardiomyocytes, and its role in cardiac function remains unexplored. Thus, we developed mice lacking Orai1 and Orai3 to address their role in cardiac homeostasis. Methods and Results We generated constitutive and inducible cardiomyocyte‐specific Orai3 knockout (Orai3 cKO ) mice. Constitutive Orai3‐loss led to ventricular dysfunction progressing to dilated cardiomyopathy and heart failure. Orai3 cKO mice subjected to pressure overload developed a fulminant dilated cardiomyopathy with rapid heart failure onset, characterized by interstitial fibrosis and apoptosis. Ultrastructural analysis of Orai3‐deficient cardiomyocytes showed abnormal M‐ and Z‐line morphology. The greater density of condensed mitochondria in Orai3‐deficient cardiomyocytes was associated with the upregulation of DRP1 (dynamin‐related protein 1). Cardiomyocytes isolated from Orai3 cKO mice exhibited profoundly altered myocardial Ca 2+ cycling and changes in the expression of critical proteins involved in the Ca 2+ clearance mechanisms. Upregulation of TRPC6 (transient receptor potential canonical type 6) channels was associated with upregulation of the RCAN1 (regulator of calcineurin 1), indicating the activation of the calcineurin signaling pathway in Orai3 cKO mice. A more dramatic cardiac phenotype emerged when Orai3 was removed in adult mice using a tamoxifen‐inducible Orai3 cKO mouse. The removal of Orai1 from adult cardiomyocytes did not change the phenotype of tamoxifen‐inducible Orai3 cKO mice. Conclusions Our results identify a critical role for Orai3 in the heart. We provide evidence that Orai3‐mediated Ca 2+ signaling is required for maintaining sarcomere integrity and proper mitochondrial function in adult mammalian cardiomyocytes.

Diacylglycerol kinase-ε restores cardiac dysfunction under chronic pressure overload: a new specific regulator of Gαq signaling cascade

2008 ◽  
Vol 295 (1) ◽  
pp. H245-H255 ◽  
Author(s):  
Takeshi Niizeki ◽  
Yasuchika Takeishi ◽  
Tatsuro Kitahara ◽  
Takanori Arimoto ◽  
Mitsunori Ishino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Heart Weight ◽  
Gpcr Signaling ◽  
Phenylephrine Infusion

Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in cardiac hypertrophy. DAG kinase (DGK) catalyzes DAG phosphorylation and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been reported that DGKε acts specifically on DAG produced by inositol cycling. In this study, we examined whether DGKε prevents cardiac hypertrophy and progression to heart failure under chronic pressure overload. We generated transgenic mice with cardiac-specific overexpression of DGKε (DGKε-TG) using an α-myosin heavy chain promoter. There were no differences in cardiac morphology and function between wild-type (WT) and DGKε-TG mice at the basal condition. Either continuous phenylephrine infusion or thoracic transverse aortic constriction (TAC) was performed in WT and DGKε-TG mice. Increases in heart weight after phenylephrine infusion and TAC were abolished in DGKε-TG mice compared with WT mice. Cardiac dysfunction after TAC was prevented in DGKε-TG mice, and the survival rate after TAC was higher in DGKε-TG mice than in WT mice. Phenylephrine- and TAC-induced DAG accumulation, the translocation of PKC isoforms, and the induction of fetal genes were blocked in DGKε-TG mouse hearts. The upregulation of transient receptor potential channel (TRPC)-6 expression after TAC was attenuated in DGKε-TG mice. In conclusion, these results demonstrate the first evidence that DGKε restores cardiac dysfunction and improves survival under chronic pressure overload by controlling cellular DAG levels and TRPC-6 expression. DGKε may be a novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure.

scholarly journals Piezo1 is the cardiac mechanosensor that initiates the hypertrophic response to pressure overload

2021 ◽  
Author(s):  
Ze-Yan Yu ◽  
Hutao Gong ◽  
Scott Kesteven ◽  
Yang Guo ◽  
Jianxin Wu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Treatment Options ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Sodium Calcium Exchanger ◽  
Hypertrophic Response ◽  
Adult Mice ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Poor Outcomes

Abstract Pressure overload-induced cardiac hypertrophy is a maladaptive response with poor outcomes and limited treatment options. The transient receptor potential melastatin 4 (TRPM4) ion channel is key to activation of a Ca2+-calmodulin kinase II (CaMKII)-dependent hypertrophic signalling pathway after pressure overload, but TRPM4 is neither stretch-activated nor Ca2+-permeable. Here we show that Piezo1, which is both stretch-activated and Ca2+-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signalling via TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice prevented activation of CaMKII and inhibited the hypertrophic response: residual hypertrophy was associated with calcineurin activation in the absence of its usual inhibition by activated CaMKII. Piezo1 deletion prevented upregulation of the sodium-calcium exchanger and downregulation of the T-type calcium channel after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, opening an avenue to novel therapies.

Abstract 11977: Tranilast, Transient Receptor Potential Vanilloid 2 Antagonist, Ameliorates End-Stage Heart Failure of Mice With Dilated Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yuko Iwata ◽  
Kazuo Komamura
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Transient Receptor Potential Vanilloid ◽  
End Stage Heart Failure ◽  
Transient Receptor ◽  
Group B ◽  
End Stage

Introduction: Abnormal intracellular Ca2+ handling seems to be involved in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). We have found up-regulation of the expression of transient receptor potential vanilloid 2 (TRPV2), a calcium-permeable cation channel, in the sarcolemma of myocardium of animal and human DCM. Hypothesis: We hypothesized an orally active TRPV2 antagonist, tranilast, ameliorated heart failure symptoms of DCM mice. Methods: We used 4C30 mice (created by National Institute of Biomedical Innovation, Japan), which has abnormal myocardial calcium handling, as a model of DCM. Sixteen 4C30 mice of 25 weeks old with end-stage heart failure were given no drug (control) or 20 mg/kg/day of carvediol (group C) or 400 mg/kg/day of tranilast (group T) or both of them (group B) for 2 weeks. Results: Blood pressure and heart rate were similar among the 4 groups. Echocardiography demonstrated tranilast improved fractional shortening (in %). Control: 6.2±2.5; Group C: 14.2±5.6, NS; Group T: 16.6±2.3, p<0.05; Group B: 17.2±3.2, p<0.05. Tranilast also improved cardiac hypertrophy measured with heart-to-body weight ratio (HW/BW in mg/g). Control: 12.4±2.5; Group C: 11.5±3.4, NS; Group T: 8.6±0.9, p<0.05; Group B: 5.9±1.1, p<0.01. Sarcolemmal expression of TRPV2 measured with immunostaining in 4C30 mice increased twice as much as syngeneic C57BL/6J. Tranilast, not carvedilol, halved the expression of TRPV2, corresponding to reduction in [Ca2+]i of isolated cardiomyocytes. Consistent with those changes, CaMKII phosphorylation reduced in the 4C30 mice after treatment of tranilast. Conclusions: Tranilast ameliorated heart failure symptoms of 4C30 mice, possibly due to the inhibition of Ca2+ influx through TRPV2.

scholarly journals TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases

2015 ◽  
Vol 309 (5) ◽  
pp. F393-F397 ◽  
Author(s):  
Daria V. Ilatovskaya ◽  
Alexander Staruschenko
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Kidney Diseases ◽  
Critical Role ◽  
Receptor Potential ◽  
Calcium Flux ◽  
Calcium Handling ◽  
Podocyte Injury ◽  
Trpc6 Channel ◽  
Transient Receptor

Podocytes (terminally differentiated epithelial cells of the glomeruli) play a key role in the maintenance of glomerular structure and permeability and in the incipiency of various renal abnormalities. Injury to podocytes is considered a major contributor to the development of kidney disease as their loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium handling; excessive calcium influx in these cells may result in the effacement of foot processes, apoptosis, and subsequent glomeruli damage. One of the key proteins responsible for calcium flux in the podocytes is transient receptor potential cation channel, subfamily C, member 6 (TRPC6); a gain-of-function mutation in TRPC6 has been associated with the onset of the familial forms of focal segmental glomerulosclerosis (FSGS). Recent data also revealed a critical role of this channel in the onset of diabetic nephropathy. Therefore, major efforts of the research community have been recently dedicated to unraveling the TRPC6-dependent effects in the initiation of podocyte injury. This mini-review focuses on the TRPC6 channel in podocytes and colligates recent data in an attempt to shed some light on the mechanisms underlying the pathogenesis of TRPC6-mediated glomeruli damage and its potential role as a therapeutic target for the treatment of chronic kidney diseases.

scholarly journals Transient Receptor Potential Melastatin 2 Negatively Regulates LPS-ATP-Induced Caspase-1-Dependent Pyroptosis of Bone Marrow-Derived Macrophage by Modulating ROS Production

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Haihong Wang ◽  
Xinyi Zhou ◽  
Hui Li ◽  
Xiaowei Qian ◽  
Yan Wang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Morphological Characteristics ◽  
Receptor Potential ◽  
Ros Production ◽  
Caspase 1 ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Background. Pyroptosis, a new form of cell death, which has special morphological characteristics, depends on caspase-1 activation and occupies an important role in inflammatory immune diseases and ischemia-reperfusion injury. ROS is a common activator of NLR/caspase-1. Transient receptor potential melastatin 2 (TRPM2), a selective cation channel, is involved in inflammatory regulation. This study was designed to explore the role of TRPM2 in activating caspase-1 and caspase-1-dependent pyroptosis of mouse BMDMs. Methods. BMDMs isolated from WT and TRPM2−/− mice were treated with LPS and ATP, along with ROS inhibitor (NAC and DPI), caspase-1 inhibitor (Z-YVAD), or not. The activation of caspase-1 was measured by western blot. EtBr and EthD-2 staining were used to assess the incidence of pyroptosis. Results. Compared with WT, the activated caspase-1-P10 was higher and the percentage of EtBr positive cells was also increased in TRPM2−/− group, which were both inhibited by Z-YVAD, NAC, or DPI. ASC oligomerization was increased in TRPM2−/− group. Conclusion. Deletion of TRPM2 can enhance the activation of caspase-1 and pyroptosis, which may be via modulating ROS production, suggesting that TRPM2 plays a critical role in immune adjustment.

Abstract 18822: Endoglin Selectively Modulates TRPC Expression in Response to Left or Right Ventricular Pressure Overload

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kevin J Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Duc T Pham ◽  
Gordon S Huggins ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Transient Receptor ◽  
Novel Target ◽  
The Right

Introduction: Endoglin is an accessory receptor for the cytokine transforming growth factor beta. Reduced endoglin activity limits cardiac fibrosis due to left ventricular (LV) pressure overload. Recently, we reported that reducing endoglin activity also limits upregulation of the profibrogenic transient receptor potential canonical channel 6 (TRPC6) in the right ventricle (RV) during pressure overload. Few studies have compared TRPC channel expression in the RV versus LV. Hypothesis: We hypothesized that endoglin regulates TRPC upregulation in response to RV and LV pressure overload. Methods: To explore a functional role for endoglin as a regulator of TRPC expression in response to RV or LV pressure overload, endoglin haploinsufficient (Eng+/-) and wild-type (Eng+/+) mice were exposed to thoracic aortic (TAC) or pulmonary arterial (PAC) constriction for 10 weeks. Biventricular tissue was then analyzed by real-time polymerase chain reaction. Results: After TAC, LV levels of TPRC1 and 6 were increased in both Eng +/+ and Eng +/- mice compared to sham controls. LV levels of TRPC4 were increased in Eng +/+, not Eng +/- mice after TAC. After PAC, RV levels of TRPC1, 3, 4, and 6 were increased in Eng +/+ compared to sham controls. In contrast, chronic RV pressure overload did not increase RV levels of TRPC1, 3, 4, and 6 in Eng +/- mice compared to sham controls. Conclusions: Pressure overload induces distinct profiles of TRPC expression in the RV and LV and these effects in the RV require full endoglin activity. Taken together, these data support that endoglin may be an important and novel target of therapy to modulate RV responses to injury.

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