Synthetic Macrocycle Nanopore for Potassium-Selective Transmembrane Transport

Abstract Background Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but so far, strategies using systemic anti-oxidants have generally failed to prevent it. Aquaporins are a family of transmembrane water channels with thirteen isoforms currently known. Some isoforms have been implicated in oxidant signaling. AQP1 is the most abundant aquaporin in cardiovascular tissues but its specific role in cardiac remodeling remains unknown. Purpose We tested the role of AQP1 as a key regulator of oxidant-mediated cardiac remodeling amenable to targeted pharmacological therapy. Methods We used mice with genetic deletion of Aqp1 (and wild-type littermate), as well as primary isolates from the same mice and human iPSC/Engineered Heart Tissue to test the role of AQP1 in pro-hypertrophic signaling. Human cardiac myocyte-specific (PCM1+) expression of AQP's and genes involved in hypertrophic remodeling was studied by RNAseq and bioinformatic GO pathway analysis. Results RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalizes with the NADPH oxidase-2 (NOX2) and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of AQP1 intra-subunit pore (with Bacopaside II) inhibits H2O2 transport in mouse and human cells and rescues the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. This protective effect is due to loss of transmembrane transport of H2O2, but not water, through the intra-subunit pore of AQP1. Treatment of mice with clinically-approved Bacopaside extract (CDRI08) inhibitor of AQP1 attenuates cardiac hypertrophy and fibrosis. Conclusion We provide the first demonstration that AQP1 functions as an aqua-peroxiporin in primary rodent and human cardiac parenchymal cells. We show that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 through the AQP1 water channel. Our studies open the way to complement the therapeutic armamentarium with specific blockers of AQP1 for the prevention of adverse remodeling in many cardiovascular diseases leading to heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FRS-FNRS, Welbio

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Myocardial CO2 buffering: role of transmembrane transport of H+ or HCO3-ions

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1976.230.4.1037 ◽

1976 ◽

Vol 230 (4) ◽

pp. 1037-1041 ◽

Cited By ~ 11

Author(s):

DR Strome ◽

RL Clancy ◽

NC Gonzalez

Keyword(s):

Small Volume ◽

Coronary Circulation ◽

Myocardial Cell ◽

Ringer Solution ◽

Red Cells ◽

Transmembrane Transport ◽

High Degree

Isolated rabbit hearts were perfused with rabbit red cells suspended in Ringer solution. A small volume of perfusate was recirculated for 10 min at Pco2 of 33.4 +/- 0.9 or 150.8 +/- 7.5 mmHg. Hypercapnia resulted in an increase in perfusate HCO3- concentration that was smaller than that observed when isolated perfusate was equilibrated in vitro with the same CO2 tensions (delta HCO-3e = 1.6 mM, P less than 0.01). This difference is consistent with a net movement of HCO3- into or H+ out of the mycardial cell, and cannot be accounted for by dilution of HCO3- in the myocardial interstitium. Recirculation of perfusate through the coronary circulation at normal Pco2 for two consecutive 10-min periods was not followed by changes in perfusate HCO3- concentration. A high degree of correlation (r = 0.81) was observed between intracellular HCO-3e concentration and the corresponding delta HCO-3e in individual experiments. The results suggest that transmembrane exchange of H+ or HCO3- is a buffer mechanism for CO2 in the myocardial cell.

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Support for a model of pH regulation by transmembrane transport

Biophysics of Structure and Mechanism ◽

10.1007/bf00647547 ◽

1980 ◽

Vol 6 (S1) ◽

pp. 75-75 ◽

Cited By ~ 2

Author(s):

U. P. Hansen ◽

W. Wittmaack

Keyword(s):

Ph Regulation ◽

Transmembrane Transport

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The Lipid Bilayer, Mechanisms of Fusion and Transmembrane Transport

Advances in Experimental Medicine and Biology - Composition and Function of Cell Membranes ◽

10.1007/978-1-4684-4112-3_4 ◽

1981 ◽

pp. 137-186

Author(s):

Stewart Wolf ◽

Allen K. Murray

Keyword(s):

Lipid Bilayer ◽

Transmembrane Transport

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Modeling Transmembrane Transport through Cell Membrane Wounds Created by Acoustic Cavitation

Biophysical Journal ◽

10.1529/biophysj.108.131664 ◽

2008 ◽

Vol 95 (9) ◽

pp. 4124-4138 ◽

Cited By ~ 44

Author(s):

Vladimir Zarnitsyn ◽

Christina A. Rostad ◽

Mark R. Prausnitz

Keyword(s):

Cell Membrane ◽

Acoustic Cavitation ◽

Transmembrane Transport

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Photomodulation of Transmembrane Transport and Potential by Stiff-Stilbene Based Bis(thio)ureas

Journal of the American Chemical Society ◽

10.1021/jacs.1c10034 ◽

2021 ◽

Author(s):

Sander J. Wezenberg ◽

Li-Jun Chen ◽

Jasper E. Bos ◽

Ben L. Feringa ◽

Ethan N. W. Howe ◽

...

Keyword(s):

Transmembrane Transport

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Obtaining and Characterization of a Polyurethane Carrier Used for Eugenol as a Possible Remedy in Oral Therapies

Materiale Plastice ◽

10.37358/mp.18.1.4953 ◽

2018 ◽

Vol 55 (1) ◽

pp. 9-13 ◽

Cited By ~ 1

Author(s):

Zoran Popa ◽

Laura Cristina Rusu ◽

Razvan Susan ◽

Iulia Pinzaru ◽

Elena Ardelean ◽

...

Keyword(s):

Drug Delivery ◽

Thermal Stability ◽

Thermal Decomposition ◽

Drug Delivery System ◽

Transmembrane Transport ◽

Vein Wall ◽

Good Thermal Stability ◽

Toxicity Effect ◽

Low Solubility

The cloves are antiseptic, antiparasitic, antibacterial, antifungal, antiviral, anesthetic, analgesic, anti-inflammatory, tonic, carminative, anti-ulcer, antithrombotic, antioxidant and anti-cancerous. They contain eugenol, tannins and flavonoids that also help to strengthen the vein wall. This paper presents the obtaining and the characterization of a polyurethane drug delivery system which can be used for the transmembrane transport of eugenol in oral therapies. The products were analyzed by pH and solubility measurements, thermal decomposition and zetasizer tests and they were applied on mice skin to evaluate their harmfulness. The results suggest that were obtained neutral pH structures with low solubility and a good thermal stability, with sizes between 241 and 289 nm and no toxicity effect was found in the case of studied samples.

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A unifying theory to describe transmembrane transport derived from thermodynamic principles

10.7287/peerj.preprints.1312v2 ◽

2015 ◽

Author(s):

Marco A Herrera-Valdez

Keyword(s):

Transmembrane Potential ◽

Functional Form ◽

Molecular Transport ◽

Planck Equation ◽

Transmembrane Transport ◽

Membrane Excitability ◽

Nonlinear Functions ◽

Functional Forms ◽

Membrane Spanning ◽

Transmembrane Currents

Herrera-Valdez. A unifying theory of physiological transmembrane transport Cellular homeostasis involves transmembrane molecular transport that is, in turn, mediated by proteins that enable molecular transport along, or against the (electro) chemical gradient of the molecules being transported. Transmembrane transport has been modelled in many studies using many functional forms that were not always derived from the same assumptions. A generic formulation that describes transmembrane fluxes regardless of whether they are mediated by carrier proteins or by open channels is presented here. The functional form of the flux was obtained from basic thermodynamic principles. Further, taking a slightly different approach, the same generic formulation mentioned above can also be obtained from the Nernst-Planck equation for the case of channel- mediated electrodiffusion. The generic formulation can be regarded as the product of an amplitude term and a driving force term, both nonlinear functions of the transmembrane concentrations of the molecules and possibly the transmembrane potential. The former captures the characteristics of the membrane-spanning protein mediating the transport and the latter is a non-linear function of the transmembrane concentrations of the ions. The generic formulation explicitly shows that the basal rate at which ions cross the membrane is the main difference between currents mediated by pumps and channels. Electrogenic transmembrane fluxes can be converted to currents to construct models of membrane excitability in which all the transmembrane currents have the same functional form. The applicability of the generic derivations presented here is illustrated with models of excitability for neurones and pacemaker cardiocytes.

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