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Review
01 March 2019
TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling
Debora Falcón
6 more and 
Tarik Smani
Scheme summarizing the role of TRP channels in cardiac fibrosis. In pathological conditions, different kind of stress stimulates Ca2+ entry in cardiac myocyte through TRP channels and other signaling pathway as RhoA dependent on reactive oxygen species (ROS) production, which lead to profibrotic gene’s expression. Profibrotic agonists and other stimuli activate cardiac fibroblast (green) leading to their proliferation and differentiation. The intracellular Ca2+ concentration increase through TRP channels promotes the expression of pro-fibrotic agonist (TGF-β1), α-SMA, collagen, and different isoforms of TRP channels, leading to exacerbated extracellular matrix synthesis and fibrosis.

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 Ca2+ 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 Ca2+ 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.

9,776 views
57 citations
8,390 views
27 citations
Original Research
21 December 2018

In a physiological setting, mitochondria increase oxidative phosphorylation during periods of stress to meet increased metabolic demand. This in part is mediated via enhanced mitochondrial Ca2+ uptake, an important regulator of cellular ATP homeostasis. In a pathophysiological setting pharmacological modulation of mitochondrial Ca2+ uptake or retention has been suggested as a therapeutic strategy to improve metabolic homeostasis or attenuate Ca2+-dependent arrhythmias in cardiac disease states. To explore the consequences of mitochondrial Ca2+ accumulation, we tested the effects of kaempferol, an activator of mitochondrial Ca2+ uniporter (MCU), CGP-37157, an inhibitor of mitochondrial Na+/Ca2+ exchanger, and MCU inhibitor Ru360 in rat ventricular myocytes (VMs) from control rats and rats with hypertrophy induced by thoracic aortic banding (TAB). In periodically paced VMs under β-adrenergic stimulation, treatment with kaempferol (10 μmol/L) or CGP-37157 (1 μmol/L) enhanced mitochondrial Ca2+ accumulation monitored by mitochondrial-targeted Ca2+ biosensor mtRCamp1h. Experiments with mitochondrial membrane potential-sensitive dye TMRM revealed this was accompanied by depolarization of the mitochondrial matrix. Using redox-sensitive OMM-HyPer and ERroGFP_iE biosensors, we found treatment with kaempferol or CGP-37157 increased the levels of reactive oxygen species (ROS) in mitochondria and the sarcoplasmic reticulum (SR), respectively. Confocal Ca2+ imaging showed that accelerated Ca2+ accumulation reduced Ca2+ transient amplitude and promoted generation of spontaneous Ca2+ waves in VMs paced under ISO, suggestive of abnormally high activity of the SR Ca2+ release channel ryanodine receptor (RyR). Western blot analyses showed increased RyR oxidation after treatment with kaempferol or CGP-37157 vs. controls. Furthermore, in freshly isolated TAB VMs, confocal Ca2+ imaging demonstrated that enhancement of mitochondrial Ca2+ accumulation further perturbed global Ca2+ handling, increasing the number of cells exhibiting spontaneous Ca2+ waves, shortening RyR refractoriness and decreasing SR Ca2+ content. In ex vivo optically mapped TAB hearts, kaempferol exacerbated proarrhythmic phenotype. On the contrary, incubation of cells with MCU inhibitor Ru360 (2 μmol/L, 30 min) normalized RyR oxidation state, improved intracellular Ca2+ homeostasis and reduced triggered activity in ex vivo TAB hearts. These findings suggest facilitation of mitochondrial Ca2+ uptake in cardiac disease can exacerbate proarrhythmic disturbances in Ca2+ homeostasis via ROS and enhanced activity of oxidized RyRs, while strategies to reduce mitochondrial Ca2+ accumulation can be protective.

6,609 views
45 citations
6,454 views
71 citations
Deficiency of NOD1 improves the modulation of systolic Ca2+ handling and SR-Ca2+ load by β-adrenergic stimulation in cardiomyocytes from failing mice. (A–C) Mean values of amplitude of [Ca2+]i transients (F/F0, A), cell contractions (CC, %, B), and caffeine-evoked [Ca2+]i transients amplitude (SR-Ca2+ load, F/F0, C) in WT (n = 13 cells/5 mice) and NOD1-/- cardiomyocytes (n = 14 cells/4 mice) with and without 10-8 M isoproterenol (Iso). (D) Representative line-scan confocal images of [Ca2+]i transients obtained from WT-PMI and NOD1-/--PMI cardiomyocytes with and without Iso perfusion. (E,F) Mean values of peak fluorescence [Ca2+]i transients (F/F0, E), cell contraction (CC, %, F), and decay time of [Ca2+]i transients (tau, ms, G) in WT-PMI (n = 12 cells/4 mice) and NOD1-/--PMI (n = 13 cells/4 mice) cardiomyocytes with and without Iso. Histograms represent the mean ± SEM: $$P < 0.01, $$$P < 0.001 vs WT; +P < 0.05 vs NOD1-/-, ++P < 0.01 vs NOD1-/-, +++P < 0.001 vs NOD1-/-; ∗P < 0.05 vs WT-PMI; &P < 0.05, &&P < 0.01, &&&P < 0.001 vs NOD1-/--PMI; and #P < 0.05, ###P < 0.001 vs WT-PMI treated with Iso.
Original Research
14 June 2018
Deficiency of NOD1 Improves the β-Adrenergic Modulation of Ca2+ Handling in a Mouse Model of Heart Failure
Almudena Val-Blasco
10 more and 
María Fernández-Velasco

Heart failure (HF) is a complex syndrome characterized by cardiac dysfunction, Ca2+ mishandling, and chronic activation of the innate immune system. Reduced cardiac output in HF leads to compensatory mechanisms via activation of the adrenergic nervous system. In turn, chronic adrenergic overstimulation induces pro-arrhythmic events, increasing the rate of sudden death in failing patients. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an innate immune modulator that plays a key role in HF progression. NOD1 deficiency in mice prevents Ca2+ mishandling in HF under basal conditions, but its role during β-adrenergic stimulation remains unknown. Here, we evaluated whether NOD1 regulates the β-adrenergic modulation of Ca2+ signaling in HF. Ca2+ dynamics were examined before and after isoproterenol perfusion in cardiomyocytes isolated from healthy and from post-myocardial infarction (PMI) wild-type (WT) and Nod1-/- mice. Isoproterenol administration induced similar effects on intracellular [Ca2+]i transients, cell contraction, and sarcoplasmic reticulum (SR)-Ca2+ load in healthy WT and Nod1-/- cells. However, compared with WT-PMI cells, isoproterenol exposure induced a significant increase in the [Ca2+]i transients and cell contraction parameters in Nod1-/--PMI cells, which mainly due to an increase in SR-Ca2+ load. NOD1 deficiency also prevented the increase in diastolic Ca2+ leak (Ca2+ waves) induced by isoproterenol in PMI cells. mRNA levels of β1 and β2 adrenergic receptors were significantly higher in Nod1-/--PMI hearts vs WT-PMI hearts. Healthy cardiomyocytes pre-treated with the selective agonist of NOD1, iE-DAP, and perfused with isoproterenol showed diminished [Ca2+]i transients amplitude, cell contraction, and SR-Ca2+ load compared with vehicle-treated cells. iE-DAP-treated cells also presented increased diastolic Ca2+ leak under β-adrenergic stimulation. The selectivity of iE-DAP on Ca2+ handling was validated by pre-treatment with the inactive analog of NOD1, iE-Lys. Overall, our data establish that NOD1 deficiency improves the β-adrenergic modulation of Ca2+ handling in failing hearts.

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Mechanisms and Novel Therapeutic Targets and Approaches for Mitochondrial Dysfunction in Neurological and Cardiovascular Diseases
Edited by Bojjibabu Chidipi, Adinarayana Marada, Qiuxia (Lisa) Li, Quanjiang Zhang
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13 April 2025
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