TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress

Jones, J. Louise; Peana, Deborah; Veteto, Adam B.; Lambert, Michelle D.; Nourian, Zahra; Karasseva, Natalia; Hill, Michael A.; Lindman, Brian R.; Baines, Christopher P.; Krenz, Maike; Domeier, Timothy L.

doi:10.1093/cvr/cvy156

Cited by 53 publications

(60 citation statements)

References 48 publications

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“…Within the atrio-ventricular region of rats sodium (Na v 1.5) are downregulated with age whilst calcium (Ca v 1.3) channels are upregulated, alongside augmented atrial-ventricular node functioning (Saeed et al, 2018). Similarly to this finding, an upregulation of L-type and osmotically activated calcium channels have been observed in human cardiomyopathy and aging, respectively (Jones et al, 2018; Sanchez-Alonso et al, 2018). An overview of ion channel dysfunctions and their relation to age-related disease is provided in Table 2.…”

Section: The Biology Of Ion Channels In Agingsupporting

confidence: 62%

Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

et al. 2019

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Aging is often associated with a loss of function. We believe aging to be more an adaptation to the various, and often continuous, stressors encountered during life in order to maintain overall functionality of the systems. The maladaptation of a system during aging may increase the susceptibility to diseases. There are basic cellular functions that may influence and/or are influenced by aging. Mitochondrial function is amongst these. Their presence in almost all cell types makes of these valuable targets for interventions to slow down or even reserve signs of aging. In this review, the role of mitochondria and essential physiological regulators of mitochondria and cellular functions, ion channels, will be discussed in the context of human aging. The origins of inflamm-aging, associated with poor clinical outcomes, will be linked to mitochondria and ion channel biology.

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Section: The Biology Of Ion Channels In Agingsupporting

confidence: 62%

Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

et al. 2019

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“…In the case of TRPV4, it is also highly expressed in the heart and is activated during myocardial ischemia and reperfusion, which induced Ca 2+ influx with subsequent reactive oxygen species (ROS) release (Wu et al., 2017). Recently, TRPV4 upregulation in cardiomyocytes was also linked with aging in mice (Jones et al., 2018). Indeed, pharmacological inhibition of TRPV4 with HC067047 prevented stress-induced cardiomyocyte death and ischemia and reperfusion-induced cardiac damage in aged mice.…”

Section: Expression Of Trp Channels In Cardiac Cellsmentioning

confidence: 99%

TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling

et al. 2019

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Calcium is an important second messenger required not only for the excitation-contraction coupling of the heart but also critical for the activation of cell signaling pathways involved in the adverse cardiac remodeling and consequently for the heart failure. Sustained neurohumoral activation, pressure-overload, or myocardial injury can cause pathologic hypertrophic growth of the heart followed by interstitial fibrosis. The consequent heart’s structural and molecular adaptation might elevate the risk of developing heart failure and malignant arrhythmia. Compelling evidences have demonstrated that Ca 2+ entry through TRP channels might play pivotal roles in cardiac function and pathology. TRP proteins are classified into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin), which are activated by numerous physical and/or chemical stimuli. TRP channels participate to the handling of the intracellular Ca 2+ concentration in cardiac myocytes and are mediators of different cardiovascular alterations. This review provides an overview of the current knowledge of TRP proteins implication in the pathologic process of some frequent cardiac diseases associated with the adverse cardiac remodeling such as cardiac hypertrophy, fibrosis, and conduction alteration.

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“…The blockade or deletion TRPV4 reduces infarct sizes and improves cardiac function (9)(10)(11)(12). In neurons, TRPV4 activation has been reported to modulate other ion currents, including voltage-gated K + currents (IK), and to result in action potential (AP) alteration (13)(14).…”

Section: Introductionmentioning

confidence: 99%

TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats

Liao¹,

Wu²,

Cheng³

et al. 2020

JCI Insight

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Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 d before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch-clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K + currents (IK), reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways, and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevents abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats, and, therefore, might be a promising strategy to treat AF, particularly post-operative AF.

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TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress

Abstract: Our findings provide a new mechanism for hypoosmotic-stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.

Cited by 53 publications

References 48 publications

Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling

TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats

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