Wilson, AD;
Richards, MA;
Curtis, MK;
Rohling, M;
Monterisi, S;
Loonat, AA;
Miller, J;
... Swietach, P; + view all
(2021)
Acidic environments trigger intracellular H+-sensing FAK proteins to re-balance sarcolemmal acid-base transporters and auto-regulate cardiomyocyte pH.
Cardiovascular Research
, Article cvab364. 10.1093/cvr/cvab364.
(In press).
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Abstract
AIMS: In cardiomyocytes, acute disturbances to intracellular pH (pHi) are promptly corrected by a system of finely-balanced sarcolemmal acid-base transporters. However, these fluxes become thermodynamically re-balanced in acidic environments, which inadvertently causes their set-point pHi to fall outside the physiological range. It is unclear whether an adaptive mechanism exists to correct this thermodynamic challenge and return pHi to normal. METHODS AND RESULTS: Following left-ventricle cryo-damage, a diffuse pattern of low extracellular pH (pHe) was detected by acid-sensing pHLIP. Despite this, pHi measured in the beating heart (13C NMR) was normal. Myocytes had adapted to their acidic environment by reducing Cl–/HCO3- exchange (CBE)-dependent acid-loading and increasing Na+/H+ exchange (NHE1)-dependent acid-extrusion, as measured by fluorescence (cSNARF1). The outcome of this adaptation on pHi is revealed as a cytoplasmic alkalinisation when cells are superfused at physiological pHe. Conversely, mice given oral bicarbonate to improve systemic buffering had reduced myocardial NHE1 expression, consistent with a needs-dependent expression of pHi-regulatory transporters. The response to sustained acidity could be replicated in vitro using neonatal ventricular myocytes (NRVMs) incubated at low pHe for 48 h. The adaptive increase in NHE1 and decrease in CBE activities was linked to Slc9a1 (NHE1) upregulation and Slc4a2 (AE2) downregulation. This response was triggered by intracellular H+ ions because it persisted in the absence of CO2/HCO3- and became ablated when acidic incubation media had low chloride concentration, a manoeuvre that reduces the extent of pHi decrease. Pharmacological inhibition of FAK-family non-receptor kinases, previously characterised as pH-sensors, ablated pHi autoregulation. In support of a pHi-sensing role, FAK protein Pyk2 (auto)phosphorylation was reduced within minutes of exposure to acidity, ahead of adaptive changes to pHi control. CONCLUSIONS: Cardiomyocytes fine-tune the expression of pHi-regulators so that pHi is at least 7.0. This autoregulatory feedback mechanism defines physiological pHi and protects it during pHe vulnerabilities. TRANSLATIONAL PERSPECTIVE: As a consequence of the inherent thermodynamic coupling between intra- and extracellular pH (pHi/pHe), sustained changes to perfusion, such as those in coronary disease or development, would have deleterious effects on the internal acid-base milieu of myocytes and hence cardiac function, unless offset by a corrective process. Using in-vivo and in-vitro models of acidification, we characterise this adaptive process functionally, and describe how it is engaged to auto-regulate pHi. This additional layer of homeostatic oversight enables the myocardium to operate within its optimal pHi-range, even at times when vascular perfusion is failing to maintain chemical constancy of the interstitial fluid.
Type: | Article |
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Title: | Acidic environments trigger intracellular H+-sensing FAK proteins to re-balance sarcolemmal acid-base transporters and auto-regulate cardiomyocyte pH |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1093/cvr/cvab364 |
Publisher version: | https://doi.org/10.1093/cvr/cvab364 |
Language: | English |
Additional information: | © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Acidity, Cardiomyocyte, Homeostasis, pH sensor, Ischemia |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10141367 |
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