Ca&lt;sup&gt;2+&lt;/sup&gt;-Activated K&lt;sup&gt;+&lt;/sup&gt; Channels as Therapeutic Targets for Myocardial and Vascular Protection

Clements, Richard; Terentyev, Dmitry; Sellke, Frank W.

doi:10.1253/circj.cj-15-0015

Cited by 19 publications

(27 citation statements)

References 65 publications

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“…The SK Ca channels family consists of three isoforms SK1 (K Ca 2.1, Kcnn1 ), SK2 (K Ca 2.2, Kcnn2 ) and SK3 (K Ca 2.3, Kcnn3 ) [44]. These three isoforms display differential distribution in the heart.…”

Section: Discussionmentioning

confidence: 99%

“…For example, SK3 activation reduced atrial fibrillation and ventricular arrhythmia [44], and electrophysiology experiments showed that overexpression of SK3 shortened the atrial action potential duration (APD) while knockdown of SK3 prolonged the APD [52]. Thus effects of SK3 channel activation on mK + uptake would be expected to alter mitochondria bioenergetics because of its effects on IMM ion homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Our results demonstrate that SK3 knockdown increases apoptosis of myocytes, and that SK3 overexpression reduces LDH release induced by HR stress. Thus SK Ca channel agonists and antagonists may be important adjuncts for therapeutic interventions in ischemic heart disease [44] and cancer [53], respectively. The SK3 knockdown effect and the in vivo rat model with infused i.v.…”

Section: Discussionmentioning

confidence: 99%

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Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Yang

Camara

Aldakkak

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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We provide evidence for location and function of a small conductance, Ca2+-activated K+ (SKCa) channel isoform 3 (SK3) in mitochondria (m) of guinea pig, rat and human ventricular myocytes. SKCa agonists protected isolated hearts and mitochondria against ischemia/reperfusion (IR) injury; SKCa antagonists worsened IR injury. Intravenous infusion of a SKCa channel agonist/antagonist, respectively, in intact rats was effective in reducing/enhancing regional infarct size induced by coronary artery occlusion. Localization of SK3 in mitochondria was evidenced by Western blot of inner mitochondrial membrane, immunocytochemical staining of cardiomyocytes, and immunogold labeling of isolated mitochondria. We identified a SK3 splice variant in guinea pig (SK3.1, aka SK3a) and human ventricular cells (SK3.2) by amplifying mRNA, and show mitochondrial expression in mouse atrial tumor cells (HL-1) by transfection with full length and truncated SK3.1 protein. We found that the Nterminus is not required for mitochondrial trafficking but the C-terminus beyond the Ca2+ calmodulin binding domain is required for Ca2+ sensing to induce mK+ influx and/or promote mitochondrial localization. In isolated guinea pig mitochondria and in SK3 overexpressed HL-1 cells, mK+ influx was driven by adding CaCl2. Moreover, there was a greater fall in membrane potential (ΔΨm), and enhanced cell death with simulated cell injury after silencing SK3.1 with siRNA. Although SKCa channel opening protects the heart and mitochondria against IR injury, the mechanism for favorable bioenergetics effects resulting from SKCa channel opening remains unclear. SKCa channels could play an essential role in restraining cardiac mitochondria from inducing oxidative stress-induced injury resulting from mCa2+ overload.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Yang

Camara

Aldakkak

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…Activation of mitoK ATP or BKCa channels results in K ϩ influx into the mitochondrial matrix. The exact mechanism of mitochondrial K ϩ flux for cardioprotection remains unclear, but possibilities include 1) electrochemical reduction of mitochondrial matrix Ca 2ϩ overload, 2) inhibition of mitochondrial permeability transition pore opening (decreased apoptosis/necrosis), 3) regulation of mitochondrial matrix volume (with subsequent regulation of respiration and/or signaling), and 4) beneficial changes in respiration and/or ROS production (12,28,35).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, the Ca 2ϩ -activated large-conductance K ϩ (BKCa) channel has also been recognized as having potent cardioprotective properties. BKCa activation reduces myocardial infarction, promotes survival, and improves cardiac and vascular function following severe ischemic insults (3,7,9,12,31,32,34,36). In addition, BKCa channels may be more potently cardioprotective than mitoK ATP channels (17).…”

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confidence: 99%

BKCa channel activation increases cardiac contractile recovery following hypothermic ischemia/reperfusion

Cordeiro

Terentyev

Clements

2015

American Journal of Physiology-Heart and Circulatory Physiology

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Cordeiro B, Terentyev D, Clements RT. BKCa channel activation increases cardiac contractile recovery following hypothermic ischemia/ reperfusion. Am J Physiol Heart Circ Physiol 309: H625-H633, 2015. First published June 12, 2015 doi:10.1152/ajpheart.00818.2014 -activated large-conductance K ϩ (BKCa) channels are thought to provide protection during ischemic insults in the heart. Rottlerin (mallotoxin) has been implicated as a potent BKCa activator. The purpose of this study was twofold: 1) to investigate the efficacy of BKCa channel activation as a cardioprotective strategy during ischemic cardioplegic arrest and reperfusion (CP/R) and 2) to assess the specificity of rottlerin for BKCa channels. Wild-type (WT) and BKCa knockout (KO) mice were subjected to an isolated heart model of ischemic CP/R. A mechanism of rottlerin-induced cardioprotection was also investigated using H9c2 cells subjected to in vitro CP/ reoxygenation and assessed for mitochondrial membrane potential and reactive oxygen species (ROS) production. CP/R decreased left ventricular developed pressure, positive and negative first derivatives of left ventricular pressure, and coronary flow (CF) in WT mice. Rottlerin dose dependently increased the recovery of left ventricular function and CF to near baseline levels. BKCa KO hearts treated with or without 500 nM rottlerin were similar to WT CP hearts. H9c2 cells subjected to in vitro CP/R displayed reduced mitochondrial membrane potential and increased ROS generation, both of which were significantly normalized by rottlerin. We conclude that activation of BKCa channels rescues ischemic damage associated with CP/R, likely via effects on improved mitochondrial membrane potential and reduced ROS generation. ischemia; mitochondria; potassium channel; reperfusion; reactive oxygen species (18,21,23,27,28,35). More recently, the Ca 2ϩ -activated large-conductance K ϩ (BKCa) channel has also been recognized as having potent cardioprotective properties. BKCa activation reduces myocardial infarction, promotes survival, and improves cardiac and vascular function following severe ischemic insults (3,7,9,12,31,32,34,36). In addition, BKCa channels may be more potently cardioprotective than mitoK ATP channels (17). NEW & NOTEWORTHYActivation of BKCa channels may also provide effective cardioprotection in the case of reversible ischemic insults associated with cardiac surgery for coronary artery bypass grafting or valve repair. Cardiac surgeries with cardioplegia and cardiopulmonary bypass provide protection to the heart and tissue from damage that could otherwise prove lethal or result in massive myocardial infarction (8,19,25). However, surgical cardioprotection is not perfect, and ischemic insults associated with cardiac surgery include reduced contractile function after surgery (myocardial stunning) and propensity for vasoconstriction and vasospasm in the coronary circulation (30).We recently demonstrated that the small molecule rottlerin (mallotoxin) enhances cardioprotection following ischemic cardioplegi...

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Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation

Carullo

Falbo

Ahmed

et al. 2023

Bioorganic Chemistry

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Ca<sup>2+</sup>-Activated K<sup>+</sup> Channels as Therapeutic Targets for Myocardial and Vascular Protection

Cited by 19 publications

References 65 publications

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

BKCa channel activation increases cardiac contractile recovery following hypothermic ischemia/reperfusion

Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation

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