Vladimir Matchkov

Involvement of transglutaminase 2 and voltage-gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries

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BACKGROUND AND PURPOSE: Vasodilatation may contribute to the neuroprotective and vascular antiremodelling effect of the tissue transglutaminase (TG2) inhibitor cystamine. The present study hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and/or inhibition of Rho kinase underlie cystamine vasodilatation.

EXPERIMENTAL APPROACH: In rat mesenteric small arteries: RT-PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca(2+) ([Ca(2+) ]i ) , K(+) currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain (MLC2).

KEY RESULTS: RT-PCR and immunoblotting revealed expression of TG2 in mesenteric small arteries. Cystamine concentration-dependently inhibited curves for phenylephrine, 5-hydroxytryptamine, U46619, and for extracellular K(+) . Selective inhibitors of TG2, LDN 27129 and T101, also inhibited phenylephrine contraction. An inhibitor of phospholipase C suppressed cystamine relaxation. Cystamine relaxed and reduced [Ca(2+) ]i in phenylephrine-contracted arteries. In potassium-contracted arteries, cystamine induced less relaxation without changing [Ca(2+) ]i , and these relaxations were blocked by mitochondrial complex inhibitors. Blockers of voltage-gated potassium KV 7 channels, XE991 and linopirdine inhibited cystamine relaxation and increases in voltage-dependent smooth muscle currents. Cystamine and the Rho kinase inhibitor Y27632 reduced basal MYPT1-Thr(855) phosphorylation, but only Y27632 reduced phenylephrine-induced increases in MYPT1-Thr(855) and MLC2 phosphorylation.

CONCLUSIONS AND IMPLICATIONS: Our findings suggest that cystamine induces vasodilatation by inhibition of receptor-coupled TG2 leading to opening of KV channels and reduction of intracellular calcium, and by activation of a pathway sensitive to inhibitors of the mitochondrial complexes I and III. Both pathways may contribute to the antihypertensive and neuroprotective effect of cystamine.

Original languageEnglish
JournalBritish Journal of Pharmacology
Pages (from-to)839-855
Number of pages17
Publication statusPublished - 1 Mar 2016

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