Acidosis and Contractility of Heart Muscle

Pa, Poole-Wilson

doi:10.1002/9780470720691.ch4

Cited by 29 publications

(20 citation statements)

References 51 publications

(18 reference statements)

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“…Although the effects of hypoxia and acidosis have been explored on I Ca by a number of investigators in adult rat ventricular myocytes, [44–47] little has been reported on the combined effects of these interventions on neonatal cardiomyocytes. While the hypoxic suppressive effects on I Ca were quantitatively different in cells with rapidly or slowly inactivating I Ca (~15% vs. ~40% suppression, respectively, Fig.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Ca2+ signaling by acute hypoxia and acidosis in rat neonatal cardiomyocytes

Fernández‐Morales¹,

Morad

2018

Journal of Molecular and Cellular Cardiology

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Our studies suggest that acute hypoxia suppresses I in rapidly inactivating cell population by a mechanism involving Ca-dependent inactivation, while compromised mitochondrial Ca uptake seems also to contribute to I suppression in slowly inactivating cell population. Proximity of cellular Ca pools to sarcolemmal Ca channels may contribute to the variability of inactivation kinetics of I in the two cell populations, while acidosis suppression of I appears mediated by proton-induced block of the calcium channel.

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Section: Discussionmentioning

confidence: 99%

Regulation of Ca2+ signaling by acute hypoxia and acidosis in rat neonatal cardiomyocytes

Fernández‐Morales¹,

Morad

2018

Journal of Molecular and Cellular Cardiology

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“…Although the consequences of hypoxia and acidosis on I Ca have been studied by a large number of labs in adult rat or guinea-pig ventricular myocytes [17,18,36,[40][41][42][43] or in rN-CMs [19,44,45] very little information has been published about the combined effects of these interventions in modulating I Ca and calcium signaling, especially in hiPSC-CMs [46]. Fig.…”

Section: Regulation Of Calcium Channels By Hypoxia or Acidosis In Hipsc-cmsmentioning

confidence: 99%

Regulation of Ca2+ signaling by acute hypoxia and acidosis in cardiomyocytes derived from human induced pluripotent stem cells

Fernández‐Morales¹,

Hua²,

Yao³

et al. 2019

Cell Calcium

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Aims:The effects of acute (100s) hypoxia and/or acidosis on Ca 2+ signaling parameters of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are explored here for the first time.Methods and Results: 1) hiPSC-CMs express two cell populations: rapidly-inactivating I Ca myocytes (τ i <40ms, in 4-5 day cultures) and slowly-inactivating I Ca (τ i ≥ 40ms, in 6-8 day cultures). 2) Hypoxia suppressed I Ca by 10-20% in rapidly-and 40-55% in slowly-inactivating I Ca cells. 3) Isoproterenol enhanced I Ca in hiPSC-CMs, but either enhanced or did not alter the hypoxic suppression. 4) Hypoxia had no differential suppressive effects in the two cell-types when Ba 2+ was the charge carrier through the calcium channels, implicating Ca 2+ -dependent inactivation in O 2 sensing. 5) Acidosis suppressed I Ca by ~35% and ~25% in rapidly and slowly inactivating I Ca cells, respectively. 6) Hypoxia and acidosis suppressive effects on Ca-transients depended on whether global or RyR2-microdomain were measured: with acidosis suppression was ~25% in global and ~37% in RyR2 Ca 2+ -microdomains in either cell type, whereas with hypoxia suppression was ~20% and ~25% respectively in global and RyR2-microdomaine in rapidly and ~35% and ~45% respectively in global and RyR2-microdomaine in slowly-inactivating cells. Conclusions:Variability in I Ca inactivation kinetics rather than cellular ancestry seems to underlie the action potential morphology differences generally attributed to mixed atrial and ventricular cell populations in hiPSC-CMs cultures. The differential hypoxic regulation of Ca 2+signaling in the two-cell types arises from differential Ca 2+ -dependent inactivation of the Ca 2+channel caused by proximity of Ca 2+ -release stores to the Ca 2+ channels.

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“…Protons accumulating with tissue acidosis can function as signaling molecules through a family of proton sensing G protein-coupled receptors (GPCRs) activated by acidic extracellular pH (~6.4–6.8); this receptor family includes G2A, GPR4, TDAG8 and OGR1 (also known as GPR68) (10–13). Myocardium’s metabolic properties make it one the most acidic (and acidosis prone) tissues in the body, yet proton sensing GPCRs have never been studied in this tissue (14). …”

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confidence: 99%

Regulated Expression of pH Sensing G Protein-Coupled Receptor-68 Identified through Chemical Biology Defines a New Drug Target for Ischemic Heart Disease

et al. 2012

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Chemical biology promises discovery of new and unexpected mechanistic pathways, protein functions and disease targets. Here, we probed the mechanism-of-action and protein targets of 3,5-disubstituted isoxazoles (Isx), cardiomyogenic small-molecules that target Notch-activated epicardium-derived cells (NECs) in vivo and promote functional recovery after myocardial infarction (MI). Mechanistic studies in NECs led to an Isx-activated Gq protein-coupled receptor (GqPCR) hypothesis tested in a cell-based functional target screen for GPCRs regulated by Isx. This screen identified one agonist hit, the extracellular proton/pH-sensing GPCR GPR68, confirmed through genetic gain- and loss-of-function. Overlooked until now, GPR68 expression and localization were highly regulated in early post-natal and adult post-infarct mouse heart, where GPR68-expressing cells accumulated subepicardially. Remarkably, GPR68-expressing cardiomyocytes established a proton sensing cellular “buffer zone” surrounding the MI. Isx pharmacologically regulated gene expression (mRNAs and miRs) in this GPR68 enriched border zone, driving cardiomyogenic and pro-survival transcriptional programs in vivo. In conclusion, we tracked a (µM) bioactive small-molecule’s mechanism-of-action to a candidate target protein, GPR68, and validated this target as a previously unrecognized regulator of myocardial cellular responses to tissue acidosis, setting the stage for future (nM) target-based drug lead discovery.

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Acidosis and Contractility of Heart Muscle

Cited by 29 publications

References 51 publications

Regulation of Ca2+ signaling by acute hypoxia and acidosis in rat neonatal cardiomyocytes

Regulation of Ca2+ signaling by acute hypoxia and acidosis in rat neonatal cardiomyocytes

Regulation of Ca2+ signaling by acute hypoxia and acidosis in cardiomyocytes derived from human induced pluripotent stem cells

Regulated Expression of pH Sensing G Protein-Coupled Receptor-68 Identified through Chemical Biology Defines a New Drug Target for Ischemic Heart Disease

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