Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 KATP channels

Chutkow, William A.; Pu, Jielin; Wheeler, Matthew T.; Wada, Tomoyuki; Makielski, Jonathan C.; Burant, Charles F.; McNally, Elizabeth M.

doi:10.1172/jci15672

Cited by 115 publications

(74 citation statements)

References 36 publications

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“…Curiously, we failed to see strong SUR2 expression in larger coronary arteries. This result is in apparent contradiction to the description that SUR2B mRNA expression occurs in larger coronaries [35] and the lack of K ATP channels in the aortic cells of the SUR2 knockout mouse [36]. Reasons for this discrepancy are unclear, but may relate to the lack of sensitivity of the anti-SUR2 antibodies used, thus underestimating SUR2 protein expression in other structures.…”

Section: Discussioncontrasting

confidence: 64%

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et al. 2005

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BackgroundElectrophysiological data suggest that cardiac KATP channels consist of Kir6.2 and SUR2A subunits, but the distribution of these (and other KATP channel subunits) is poorly defined. We examined the localization of each of the KATP channel subunits in the mouse and rat heart.ResultsImmunohistochemistry of cardiac cryosections demonstrate Kir6.1 protein to be expressed in ventricular myocytes, as well as in the smooth muscle and endothelial cells of coronary resistance vessels. Endothelial capillaries also stained positive for Kir6.1 protein. Kir6.2 protein expression was found predominantly in ventricular myocytes and also in endothelial cells, but not in smooth muscle cells. SUR1 subunits are strongly expressed at the sarcolemmal surface of ventricular myocytes (but not in the coronary vasculature), whereas SUR2 protein was found to be localized predominantly in cardiac myocytes and coronary vessels (mostly in smaller vessels). Immunocytochemistry of isolated ventricular myocytes shows co-localization of Kir6.2 and SUR2 proteins in a striated sarcomeric pattern, suggesting t-tubular expression of these proteins. Both Kir6.1 and SUR1 subunits were found to express strongly at the sarcolemma. The role(s) of these subunits in cardiomyocytes remain to be defined and may require a reassessment of the molecular nature of ventricular KATP channels.ConclusionsCollectively, our data demonstrate unique cellular and subcellular KATP channel subunit expression patterns in the heart. These results suggest distinct roles for KATP channel subunits in diverse cardiac structures.

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Section: Discussioncontrasting

confidence: 64%

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et al. 2005

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“…Using cardiac specific disruption of K ATP channels avoids potential unwanted systemic effects of global gene deletion such as insulin secretion defects 28 or coronary spasm 29 that have been described in other global K ATP gene deficient mouse strains. To confirm that our observations were caused by K ATP ablation, we also studied the effects of global depletion of the pore forming subunit in Kir6.2 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Sarcolemmal ATP-Sensitive Potassium Channel Activity Impairs the Cardiac Response to Systolic Overload

Huang

et al. 2008

Circulation Research

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Abstract-Sarcolemmal ATP-sensitive potassium channels (K ATP ) act as metabolic sensors that facilitate adaptation of the left ventricle to changes in energy requirements. This study examined the mechanism by which K ATP dysfunction impairs the left ventricular response to stress using transgenic mouse strains with cardiac-specific disruption of K ATP activity (SUR1-tg mice) or Kir6. A TP-sensitive potassium channels (K ATP ) act as metabolic sensors that can regulate cellular activity to meet energetic demands. 1 In the cardiac myocyte, K ATP channels are composed of the pore forming subunit Kir6.2 and the regulatory subunit SUR2A. Patients with missense or frameshift mutations in genes encoding the cardiac K ATP channel are predisposed to cardiomyopathy or sudden death. 2,3 Moreover, in genetically modified mouse models, global Kir6.2 gene knockout (Kir6.2 KO) resulted in abolition of ischemic preconditioning, 4 reduced exercise capacity, 5 impaired the response to adrenergic challenge, 6 compromised the tolerance to hypertension, 7 and impaired the ability to tolerate hemodynamic overload produced by transverse aortic constriction (TAC). 8 Two recent studies using Kir6.2 KO mice reported that disruption of K ATP channel activity led to activation of calcium-dependent calcineurin pathways, which, in turn, increased nuclear accumulation of the prohypertrophic transcription factors MEF2 and NFAT. 7,8 However, the molecular mechanisms by which K ATP channels regulate cardiac function, particularly during adaptation of the heart to the increased metabolic requirements produced by hemodynamic overload, are largely unknown. Most importantly, as a well defined metabolic stress sensor, the role of K ATP channels in regulation of genes related to myocardial metabolism has not been studied.At the transcriptional level, several families of transcription factors have been identified that regulate energy production processes, including peroxisome proliferator-activated receptor (PPAR), 9 estrogen-related receptor (ERR), 10,11 nuclear respiratory factor (NRF), 12 Tfam (mitochondrial transcription factor A), 13 PPAR␥ coactivator-1␣ (PGC-1␣), and PGC-1␤. 14 PGC-1␣ and PGC-1␤ bind to both nuclear receptors and nonnuclear receptors and control cellular energy metabolic pathways. In transgenic mice, overexpression of Original

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“…K ATP channels are found in many tissue types, including the pancreatic β-cell (Ashcroft et al, 1984; Findlay et al, 1985), brain (Ashford et al, 1988), and striated and smooth muscle (Spruce et al, 1985; Standen et al, 1989), with different tissues expressing K ATP channels with differing physiological properties. The critical roles that K ATP channels play have been highlighted by K ATP mutations that underlie several important human diseases, including hyperinsulinism, diabetes (Masia et al, 2007; Shimomura, 2009; Sivaprasadarao et al, 2007), heart disease (Bienengraeber et al, 2004; Kane et al, 2005; Miki and Seino, 2005), and hypertension (Chutkow et al, 2002; Kane et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

The ATP-sensitive K+-channel (KATP) controls early left–right patterning in Xenopus and chick embryos

Koster

Pearson

et al. 2010

Developmental Biology

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Consistent left-right asymmetry requires specific ion currents. We characterize a novel laterality determinant in Xenopus laevis: the ATP-sensitive K+-channel (KATP). Expression of specific dominant-negative mutants of the Xenopus Kir6.1 pore subunit of the KATP channel induced randomization of asymmetric organ positioning. Spatio-temporally controlled loss-of-function experiments revealed that the KATP channel functions asymmetrically in LR patterning during very early cleavage stages, and also symmetrically during the early blastula stages, a period when heretofore largely unknown events transmit LR patterning cues. Blocking KATP channel activity randomizes the expression of the left-sided transcription of Nodal. Immunofluorescence analysis revealed that XKir6.1 is localized to basal membranes on the blastocoel roof and cell-cell junctions. A tight junction integrity assay showed that KATP channels are required for proper tight junction function in early Xenopus embryos. We also present evidence that this function may be conserved to the chick, as inhibition of KATP in the primitive streak of chick embryos randomizes the expression of the left-sided gene Sonic hedgehog. We propose a model by which KATP channels control LR patterning via regulation of tight junctions.

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Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 KATP channels

Cited by 115 publications

References 36 publications

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Disruption of Sarcolemmal ATP-Sensitive Potassium Channel Activity Impairs the Cardiac Response to Systolic Overload

The ATP-sensitive K+-channel (KATP) controls early left–right patterning in Xenopus and chick embryos

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