Activation of transient receptor potential vanilloid 4 is involved in pressure overload-induced cardiac hypertrophy
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Evaluation Summary:
This study investigated the role of transient receptor potential vanilloid 4 (TRPV4) in pressure overload-induced cardiac hypertrophy. The expression of TPRV4 is increased in both heart failure and pressure overload-induced cardiac hypertrophy models. The TRPV4 deletion or inhibition ameliorated the hypertrophy cardiac pathology. The authors propose that TRPV4 is a potential therapeutic target for cardiac hypertrophy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Abstract
Previous studies, including our own, have demonstrated that transient receptor potential vanilloid 4 (TRPV4) is expressed in hearts and implicated in cardiac remodeling and dysfunction. However, the effects of TRPV4 on pressure overload-induced cardiac hypertrophy remain unclear. In this study, we found that TRPV4 expression was significantly increased in mouse hypertrophic hearts, human failing hearts, and neurohormone-induced hypertrophic cardiomyocytes. Deletion of TRPV4 attenuated transverse aortic constriction (TAC)-induced cardiac hypertrophy, cardiac dysfunction, fibrosis, inflammation, and the activation of NFκB - NOD - like receptor pyrin domain-containing protein 3 (NLRP3) in mice. Furthermore, the TRPV4 antagonist GSK2193874 (GSK3874) inhibited cardiac remodeling and dysfunction induced by TAC. In vitro, pretreatment with GSK3874 reduced the neurohormone-induced cardiomyocyte hypertrophy and intracellular Ca 2+ concentration elevation. The specific TRPV4 agonist GSK1016790A (GSK790A) triggered Ca 2+ influx and evoked the phosphorylation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). But these effects were abolished by removing extracellular Ca 2+ or GSK3874. More importantly, TAC or neurohormone stimulation-induced CaMKII phosphorylation was significantly blocked by TRPV4 inhibition. Finally, we show that CaMKII inhibition significantly prevented the phosphorylation of NFκB induced by GSK790A. Our results suggest that TRPV4 activation contributes to pressure overload-induced cardiac hypertrophy and dysfunction. This effect is associated with upregulated Ca 2+ /CaMKII mediated activation of NFκB-NLRP3. Thus, TRPV4 may represent a potential therapeutic drug target for cardiac hypertrophy and dysfunction after pressure overload.
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Evaluation Summary:
This study investigated the role of transient receptor potential vanilloid 4 (TRPV4) in pressure overload-induced cardiac hypertrophy. The expression of TPRV4 is increased in both heart failure and pressure overload-induced cardiac hypertrophy models. The TRPV4 deletion or inhibition ameliorated the hypertrophy cardiac pathology. The authors propose that TRPV4 is a potential therapeutic target for cardiac hypertrophy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel that mediates the influx of extracellular Ca2+, subsequently, activates the intracellular Ca2+-triggered signaling cascades. The expression of TRPV4 is increased in several cardiac pathologies such as pressure overload, aging, ischemia-reperfusion, and heart failure. TRPV4 inhibitor ameliorated pulmonary edema associated with heart failure in animal models. Early phase clinical trial for TRPV4 as a potential treatment for heart failure has been done with promising results.
In this study, the authors showed the upregulated TRPV4 in the hearts of pressure overload mice model and heart failure patients. Deletion and inhibition of TRPV4 improved cardiomyocyte hypertrophy both in-vivo and in-vitro in the TAC model and angiotensin …Reviewer #1 (Public Review):
Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel that mediates the influx of extracellular Ca2+, subsequently, activates the intracellular Ca2+-triggered signaling cascades. The expression of TRPV4 is increased in several cardiac pathologies such as pressure overload, aging, ischemia-reperfusion, and heart failure. TRPV4 inhibitor ameliorated pulmonary edema associated with heart failure in animal models. Early phase clinical trial for TRPV4 as a potential treatment for heart failure has been done with promising results.
In this study, the authors showed the upregulated TRPV4 in the hearts of pressure overload mice model and heart failure patients. Deletion and inhibition of TRPV4 improved cardiomyocyte hypertrophy both in-vivo and in-vitro in the TAC model and angiotensin II/PE treated NVRMs, respectively. Mechanistically, TRPV4 activation induced cardiac hypertrophy, inflammation, and fibrosis via Ca2+ influx which augmented CaMKII phosphorylation and subsequently activated the NFkB pathway. All of which were blocked by TRPV4 antagonism and thus cardiac function was improved.Strength
This study is methodologically robust, combining both in vivo and in vitro experiments with convincing data and appropriate statistical analysis.Weakness
The scientific merit of this study may be limited since TRPV4 has been studied for over two decades, and there are several studies have been done concerning heart failure. -
Reviewer #2 (Public Review):
This study is well-performed, methods and controls are adequate, and the manuscript is well-written. The authors combined in vitro experimental approaches with a preclinical in vivo model and human samples. The data reveal that mechanosensitive calcium channel TRPV4 is a critical driver in a preclinical model of hypertrophy and its activation induces a pro-inflammatory changes on mRNA and protein level in myocytes through CAMKII/NFkB p65 signaling.
The conclusions of this manuscript are well supported by data in a comprehensive and translational study. My main concerns relate i) to the missing attempt to show a clinically relevant intervention, ii) to the choice of the genetic model, iii) to a lack to critically discuss the role of endothelial TRPV4 in this model, iii) and the missing clinical background …
Reviewer #2 (Public Review):
This study is well-performed, methods and controls are adequate, and the manuscript is well-written. The authors combined in vitro experimental approaches with a preclinical in vivo model and human samples. The data reveal that mechanosensitive calcium channel TRPV4 is a critical driver in a preclinical model of hypertrophy and its activation induces a pro-inflammatory changes on mRNA and protein level in myocytes through CAMKII/NFkB p65 signaling.
The conclusions of this manuscript are well supported by data in a comprehensive and translational study. My main concerns relate i) to the missing attempt to show a clinically relevant intervention, ii) to the choice of the genetic model, iii) to a lack to critically discuss the role of endothelial TRPV4 in this model, iii) and the missing clinical background information since the investigated cohort of patients is quite small.
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