Slick K+ channels contribute to cardiac remodeling, fibrosis, and dysfunction in postinfarction hearts
Jiaqi Yang, Lin Zhu, David Spähn, Melanie Cruz Santos, Sophia Schanz, Selina Maier, Lena Birkenfeld, Helmut Bischof, Anna Roslan, Nina Wettschureck, Oliver Borst, Lucas Matt, Robert Lukowski
Jiaqi Yang, Lin Zhu, David Spähn, Melanie Cruz Santos, Sophia Schanz, Selina Maier, Lena Birkenfeld, Helmut Bischof, Anna Roslan, Nina Wettschureck, Oliver Borst, Lucas Matt, Robert Lukowski
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Research Article Cardiology Cell biology

Slick K+ channels contribute to cardiac remodeling, fibrosis, and dysfunction in postinfarction hearts

Abstract

Resident cardiac fibroblast–derived (RCF-derived) cardiac myofibroblasts (CMFs) contribute to myocardial repair but also drive adverse ventricular remodeling and contractile dysfunction after myocardial infarction (MI). The sodium-activated potassium channel Slick (Slo2.1) has been described in cardiomyocyte (CM) mitochondria; however, transcriptomic analyses indicate higher Slick expression in RCFs/CMFs. Here, we investigated the role of Slick in cardiac fibroblast function and post-MI remodeling. Using live-cell imaging and whole-cell patch-clamp recordings, we found that plasma membrane Slick channels in RCFs and CMFs regulated potassium (K+) efflux and modulated store-operated calcium entry (SOCE), particularly in CMFs. Global Slick KO and conditional CMF-specific KO hearts exhibited reduced fibrosis and preserved left ventricular function after ischemia/reperfusion injury. This cardioprotection was associated with diminished CMF activation and proliferation, reduced inflammation, and improved CM survival after MI. Collectively, these findings identify fibroblast Slick channels as regulators of SOCE-dependent fibrogenesis and demonstrate that their deletion mitigates maladaptive remodeling and functional decline after MI.

Authors

Jiaqi Yang, Lin Zhu, David Spähn, Melanie Cruz Santos, Sophia Schanz, Selina Maier, Lena Birkenfeld, Helmut Bischof, Anna Roslan, Nina Wettschureck, Oliver Borst, Lucas Matt, Robert Lukowski

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Figure 2

Loss of Slick in RCFs and CMFs disrupts [Ca2+]i dynamics.

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Loss of Slick in RCFs and CMFs disrupts [Ca2+]i dynamics. (A) Normalized...
(A) Normalized average 340 nm/380 nm ratios over time in RCFs during [Ca2+]ex depletion. (B) Δ [Ca2+]i (Rmax – Rmin) in WT and KO RCFs. Mann-Whitney U test, *P < 0.05 (n = 4 hearts per genotype). (C) Normalized average 340 nm/380 nm ratios in CMFs during [Ca2+]ex depletion. (D) Δ [Ca2+]i in WT and Slick KO CMFs. Two-tailed unpaired Student’s t test, **P < 0.01 (n = 4 hearts per genotype). (E) Normalized average 340 nm/380 nm ratios in RCFs during niclosamide treatment. (F) Δ [Ca2+]i (R20min – R5min) in WT and KO RCFs. Two-tailed unpaired Student’s t test, *P < 0.05 (n = 10 hearts per genotype). (G) Normalized average 340 nm/380 nm ratios in CMFs during niclosamide treatment. (H) Δ [Ca2+]i in WT and Slick KO CMFs. Mann-Whitney U test, **P < 0.01 (n = 10 hearts per genotype). (I) Normalized average 340 nm/380 nm ratios during SOCE in RCFs. SOCE was induced by ER Ca2+ depletion with BHQ, followed by re-addition of 2 mM [Ca2+]ex. Niclosamide was applied to open Slick channels 5 minutes after baseline recording. (J) Δ SOCE (Rmax – Rmin during Ca2+ re-addition) in WT and Slick KO RCFs. Two-tailed unpaired Student’s t test (n = 8 hearts per genotype). (K) Normalized average 340 nm/380 nm ratios during SOCE in CMFs. (L) Δ SOCE in WT and Slick KO CMFs. Two-tailed unpaired Student’s t test, *P < 0.05 (n = 8 hearts per genotype).