Korean J Physiol Pharmacol.  2021 May;25(3):227-237. 10.4196/kjpp.2021.25.3.227.

Carbon monoxide activates large-conductance calcium-activated potassium channels of human cardiac fibroblasts through various mechanisms

• Bae H
• Kim T
• Lim I

• KMID: 2514948
• DOI: http://doi.org/10.4196/kjpp.2021.25.3.227

Abstract

Carbon monoxide (CO) is a cardioprotectant and potential cardiovascular therapeutic agent. Human cardiac fibroblasts (HCFs) are important determinants of myocardial structure and function. Large-conductance Ca ²⁺ -activated K⁺ (BK) channel is a potential therapeutic target for cardiovascular disease. We investigated whether CO modulates BK channels and the signaling pathways in HCFs using whole-cell mode patch-clamp recordings. CO-releasing molecules (CORMs; CORM-2 and CORM-3) significantly increased the amplitudes of BK currents IBK. The CO-induced stimulating effects on IBK were blocked by pre-treatment with specific nitric oxide synthase (NOS) blockers (L-N ^G -monomethyl arginine citrate and L-N ^G -nitroarginine methyl ester). 8-bromo-cyclic GMP increased IBK. KT5823 (inhibits PKG) or ODQ (inhibits soluble guanylate cyclase) blocked the CO-stimulating effect on IBK. Moreover, 8-bromo-cyclic AMP also increased IBK, and pre-treatment with KT5720 (inhibits PKA) or SQ22536 (inhibits adenylate cyclase) blocked the CO effect. Pre-treatment with Nethylmaleimide (a thiol-alkylating reagent) also blocked the CO effect on IBK, and DLdithiothreitol (a reducing agent) reversed the CO effect. These data suggest that CO activates IBK through NO via the NOS and through the PKG, PKA, and S-nitrosylation pathways.

Keyword

Calcium-activated potassium channel; Carbon monoxide; Nitric oxide; Protein kinases

Figure

• 

  Fig. 1 Effects of carbon monoxide (CO) on large-conductance Ca2+-activated K+ currents of HCFs. (A) Original recordings of K+ outward currents were obtained by repeated voltage step depolarization from −80 to +50 mV for 400 ms (holding potential, –80 mV) before (control) and after the application of CO-releasing molecules (CORMs; CORM-2 or CORM-3, 10 μM, each) in whole-cell mode patch-clamp recordings. Paxilline (10 μM) was added to confirm IBK. (B) Summarized current–voltage (I–V) curves for the effects of CO donors and paxilline show a strong outward rectification that characterizes IBK. Values are mean ± SEM. **p < 0.01, ***p < 0.001 compared to control (n = 10, each). (C) Bar graphs showing the summary of the current density changes at +50 mV regarding the effects of CORM-2, CORM-3, and paxilline (n = 10, each). (D) Concentration-dependent activation curves of IBK by CORM-2 and CORM-3 are shown. The solid line shows the fit based on a standard dose-response relationship, which yielded an estimated half maximal effective concentration (EC50) of 9.8 μM for CORM-2 and 10.9 μM for CORM-3.

• 

  Fig. 2 Effect of nitric oxide synthase (NOS) blockers on CO-releasing molecule (CORM)-induced IBK activation. (A) Summarized current–voltage (I–V) curves for the effects of CORM-2 or CORM-3 after L-NG-monomethyl arginine citrate (L-NMMA, an NOS blocker, 100 μM) pre-treatments. IBK was confirmed by 10 μM paxilline. (B) Bar graphs show the summary of the current density changes regarding the effects of CORM-2 or CORM-3 (10 μM, each) after L-NMMA (100 μM) pre-treatments at +50 mV. ***p < 0.001 paxilline vs. control (n = 10, each). (C) Summarized I–V curves for the effects of CORM-2 or CORM-3 after L-NG-nitroarginine methyl ester (L-NAME, an NOS blocker, 100 μM) pre-treatments. (D) Bar graphs showing the summary of the current density changes regarding the effects of CORM-2 or CORM-3 after L-NAME pre-treatments at +50 mV (n = 12, each).

• 

  Fig. 3 Effect of cGMP signaling pathways on carbon monoxide (CO)-induced IBK activation in human cardiac fibroblasts (HCFs). (A) Representative currents and current–voltage (I–V) curves show the summarized current density changes for the effect of 300 μM 8-Br-cGMP on IBK, n = 8, **p < 0.01 vs. the control. (B) Bar graphs show the summary of the current density changes regarding the effect of 8-Br-cGMP (300 μM) at +50 mV. Values are mean ± SEM. (C) I–V curves and (D) bar graphs also showing the summarized current density changes for the effect of pre-treatment with KT5823 (1 μM, a PKG blocker) for 20 min for IBK activation induced by CO-releasing molecule (CORM)-2 (10 μM, n = 12) or CORM-3 (10 μM, n = 8). (E) I–V curves and (F) bar graphs also showing the summarized current density changes for the effect of 10 μM CORM-2 (n = 12) or 10 μM CORM-3 (n = 8) on IBK after pre-treatment with 1 μM ODQ, a specific soluble guanylate cyclase (sGC) blocker.

• 

  Fig. 4 Effect of the cAMP signaling pathway on the carbon monoxide (CO)-induced IBK activation of human cardiac fibroblasts (HCFs). (A) Representative currents and current–voltage (I–V) curves showing the summary of the current density changes regarding the effect of 8-Br-cAMP (300 μM) on IBK (n = 8, *p < 0.05, **p < 0.01 vs. the control). (B) Bar graphs at +50 mV show the summarized current density changes by 8-Br-cAMP (300 μM, n = 8) on the IBK. (C) I–V curves and (D) bar graphs show the summarized current density changes for the effect of 10 μM CO-releasing molecule (CORM)-2 (n = 8) or 10 μM CORM-3 (n = 8) on IBK after pre-treatment with KT5720 (1 μM) for 20 min. (E) I–V curves and (F) bar graphs show the summarized current density changes for the effect of 10 μM CORM-2 (n = 8) or 10 μM CORM-3 (n = 8) on IBK after pre-treatment with SQ22536 (1 μM) for 20 min.

• 

  Fig. 5 Effect of S-nitrosylation on carbon monoxide (CO)-induced IBK activation. (A) Current–voltage (I–V) curves from –60 to +50 mV and (B) bar graphs at +50 mV showing the summarized current density changes by CO-releasing molecule (CORM)-2 (10 μM, n = 6) or CORM-3 (10 μM, n = 6) on IBK after pre-treatment with N-ethylmaleimide (NEM, a thiol-alkylating reagent, 0.5 mM). (C) I–V curves and (D) bar graphs showing the summarized current density changes for the effect of CORM-2 (n = 6) or CORM-3 (n = 6) on IBK after pre-treatment with DL-dithiothreitol (DTT, a reducing agent; 5 mM). *p < 0.05, **p < 0.01 vs. the control, #p < 0.05 vs. CORMs.

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