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.

scholarly journals The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yang Guo ◽  
Ze-Yan Yu ◽  
Jianxin Wu ◽  
Hutao Gong ◽  
Scott Kesteven ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Transient Receptor Potential ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Mechanical Stretch ◽  
Initial Step ◽  
Left Ventricular ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Trpm4 Channel

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.

scholarly journals Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel

2021 ◽  
Vol 9 ◽  
Author(s):  
Tian Jia ◽  
Xiaozhi Wang ◽  
Yiqun Tang ◽  
Wenying Yu ◽  
Chenhui Li ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Receptor Potential ◽  
Transforming Growth Factor Β ◽  
Permeable Channel ◽  
Transient Receptor ◽  
Tgf Β1

Heart failure caused by cardiac fibrosis has become a major challenge of public health worldwide. Cardiomyocyte programmed cell death (PCD) and activation of fibroblasts are crucial pathological features, both of which are associated with aberrant Ca2+ influx. Transient receptor potential cation channel subfamily M member 7 (TRPM7), the major Ca2+ permeable channel, plays a regulatory role in cardiac fibrosis. In this study, we sought to explore the mechanistic details for sacubitril, a component of sacubitril/valsartan, in treating cardiac fibrosis. We demonstrated that sacubitril/valsartan could effectively ameliorate cardiac dysfunction and reduce cardiac fibrosis induced by isoprotereno (ISO) in vivo. We further investigated the anti-fibrotic effect of sacubitril in fibroblasts. LBQ657, the metabolite of sacubitril, could significantly attenuate transforming growth factor-β 1 (TGF-β1) induced cardiac fibrosis by blocking TRPM7 channel, rather than suppressing its protein expression. In addition, LBQ657 reduced hypoxia-induced cardiomyocyte PCD via suppression of Ca2+ influx regulated by TRPM7. These findings suggested that sacubitril ameliorated cardiac fibrosis by acting on both fibroblasts and cardiomyocytes through inhibiting TRPM7 channel.

Abstract 292: TRPA1 Promoting Myofibroblast Differentiation Mediate Pressure Overload-Induced Cardiac Fibrosis

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Shuang Li ◽  
Dong Han ◽  
Dachun Yang
Keyword(s):  
Knockout Mice ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Gene Transfection ◽  
Pressure Overload

Background: Hypertensive ventricular remodeling is a common cause of heart failure. Activation and accumulation of cardiac fibroblasts is the key contributors to this progression. Our previous studies indicate that transient receptor potential ankyrin 1 (TRPA1), a Ca 2+ channel necessary and sufficient, play a prominent role in ventricular remodeling. However, the molecular mechanisms regulating remain poorly understood. Methods: We used TRPA1 agonists cinnamaldehyde (CA) pretreatment and TRPA1 knockout mice to understand the role of TRPA1 in ventricular remodeling of hypertensive heart. We also examine the mechanisms through gene transfection and in vitro experiments. Results: TRPA1 overexpression fully activated myofibroblast transformation, while fibroblasts lacking TRPA1 were refractory to transforming growth factor β (TGF-β) -induced transdifferentiation. TRPA1 knockout mice showed hypertensive ventricular remodeling reversal following pressure overload. We found that the TGF-β induced TRPA1 expression through calcineurin-NFAT-Dyrk1A signaling pathway via the TRPA1 promoter. Once induced, TRPA1 activates the Ca 2+ -responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPA1-dependent transdifferentiation. Conclusion: Our study provides the first evidence that TRPA1 regulation in cardiac fibroblasts transformation in response to hypertensive stimulation. The results suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-β, Calcineurin, NFAT and Dyrk1A. Furthermore, these data indicate that negative modulation of cardiac fibroblast TRPA1 may represent a therapeutic strategy against hypertensive cardiac remodeling.

scholarly journals Transient Receptor Potential Cation Channel 6 (TRPC6) Contributes to Kidney Injury Induced by Diabetes and Hypertension

2021 ◽  
Author(s):  
Zhen Wang ◽  
Yiling Fu ◽  
Jussara M. do Carmo ◽  
Alexandre A. da Silva ◽  
Xuan Li ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Cell Injury ◽  
Apoptotic Cell ◽  
Kidney Injury ◽  
Receptor Potential ◽  
Cation Channel ◽  
Kidney Dysfunction ◽  
Albumin Excretion ◽  
Transient Receptor ◽  
The Right

Diabetes (DM) and hypertension (HTN) are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed whether DM and HTN interact synergistically to promote kidney dysfunction and if Transient Receptor Potential Cation Channel 6 (TRPC6) contributes to this synergism. In wild type (WT; B6/129s background) and TRPC6 knockout (KO) mice, DM was induced by streptozotocin injection to increase fasting glucose levels to 250-350 mg/dL. HTN was induced by aorta constriction (AC) between the renal arteries. AC increased blood pressure (BP) by ~25 mmHg in the right kidney (above AC) while BP in the left kidney (below AC) returned to near normal after 8 weeks, with both kidneys exposed to the same levels of blood glucose, circulating hormones, and neural influences. Kidneys of WT mice exposed to DM or HTN alone had only mild glomerular injury and urinary albumin excretion. In contrast, kidneys exposed to DM plus HTN (WT-DM+AC mice) for 8 weeks had much greater increases in albumin excretion and histological injury. Marked increased apoptosis was also observed in the right kidneys of WT-DM+AC mice. In contrast, in TRPC6 KO-DM+AC mice, the right kidneys exposed to the same levels of high BP and high glucose had lower albumin excretion, less glomerular damage and apoptotic cell injury compared to right kidneys of WT-DM+AC mice. Our results suggest that TRPC6 may contribute to the interaction of DM and HTN to promote kidney dysfunction and apoptotic cell injury.

scholarly journals Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis

Haematologica ◽  
2019 ◽  
Vol 105 (11) ◽  
pp. 2572-2583
Author(s):  
Shaoxin Yang ◽  
Wei Lu ◽  
Chong Zhao ◽  
Yuanmei Zhai ◽  
Yanyu Wei ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Receptor Potential ◽  
Transforming Growth Factor Β ◽  
Leukemia Cells ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor ◽  
Novel Strategy ◽  
And Function

Remodeling of adipocyte morphology and function plays a critical role in prostate cancer development. We previously reported that leukemia cells secrete growth differentiation factor 15 (GDF15)，which remodels the residual bone marrow (BM) adipocytes into small adipocytes and is associated with a poor prognosis in acute myeloid leukemia (AML) patients. However, little is known about how GDF15 drives BM adipocyte remodeling. In this study, we examined the role of the transient receptor potential vanilloid (TRPV) channels in the remodeling of BM adipocytes exposed to GDF15. We found that TRPV4 negatively regulated GDF15-induced remodeling of BM adipocytes. Furthermore, transforming growth factor-β type II receptor (TGFβRII) was identified as the main receptor for GDF15 on BM adipocytes. PI3K inhibitor treatment reduced GDF15-induced pAKT, identifying PI3K/AKT as the downstream stress response pathway. Subsequently, GDF15 reduced the expression of the transcription factor Forkhead box C1 (FOXC1) in BM adipocytes subjected to RNA-seq screening and Western blot analyse. Moreover, it was also confirmed that FOXC1 combined with the TRPV4 promoter by the Chip-qPCR experiments, which suggests that FOXC1 mediates GDF15 regulation of TRPV4. In addition, an AML mouse model exhibited smaller BM adipocytes, whereas the TRPV4 activator 4α-phorbol 12,13-didecanoate (4αPDD) partly rescued this process and increased survival. In conclusion, TRPV4 plays a critical role in BM adipocyte remodeling induced by leukemia cells, suggesting that targeting TRPV4 may constitute a novel strategy for AML therapy.

scholarly journals Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents

2009 ◽  
Vol 158 (6) ◽  
pp. 1621-1628 ◽  
Author(s):  
E Andrè ◽  
R Gatti ◽  
M Trevisani ◽  
D Preti ◽  
PG Baraldi ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor ◽  
Novel Target

scholarly journals Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy

2017 ◽  
Vol 114 (50) ◽  
pp. E10763-E10771 ◽  
Author(s):  
Heaseung Sophia Chung ◽  
Grace E. Kim ◽  
Ronald J. Holewinski ◽  
Vidya Venkatraman ◽  
Guangshuo Zhu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
The Impact

Duchenne muscular dystrophy (DMD) is an X-linked disorder with dystrophin loss that results in skeletal and cardiac muscle weakening and early death. Loss of the dystrophin–sarcoglycan complex delocalizes nitric oxide synthase (NOS) to alter its signaling, and augments mechanosensitive intracellular Ca2+ influx. The latter has been coupled to hyperactivation of the nonselective cation channel, transient receptor potential canonical channel 6 (Trpc6), in isolated myocytes. As Ca2+ also activates NOS, we hypothesized that Trpc6 would help to mediate nitric oxide (NO) dysregulation and that this would be manifest in increased myocardial S-nitrosylation, a posttranslational modification increasingly implicated in neurodegenerative, inflammatory, and muscle disease. Using a recently developed dual-labeling proteomic strategy, we identified 1,276 S-nitrosylated cysteine residues [S-nitrosothiol (SNO)] on 491 proteins in resting hearts from a mouse model of DMD (dmdmdx:utrn+/−). These largely consisted of mitochondrial proteins, metabolic regulators, and sarcomeric proteins, with 80% of them also modified in wild type (WT). S-nitrosylation levels, however, were increased in DMD. Genetic deletion of Trpc6 in this model (dmdmdx:utrn+/−:trpc6−/−) reversed ∼70% of these changes. Trpc6 deletion also ameliorated left ventricular dilation, improved cardiac function, and tended to reduce fibrosis. Furthermore, under catecholamine stimulation, which also increases NO synthesis and intracellular Ca2+ along with cardiac workload, the hypernitrosylated state remained as it did at baseline. However, the impact of Trpc6 deletion on the SNO proteome became less marked. These findings reveal a role for Trpc6-mediated hypernitrosylation in dmdmdx:utrn+/− mice and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease.

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