Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

Stoller, Douglas; Kakkar, Rahul; Smelley, Matthew; Chalupský, Karel; Earley, Judy U.; Shi, Nian‐Qing; Makielski, Jonathan C.; McNally, Elizabeth M.

doi:10.1016/j.yjmcc.2007.07.058

Cited by 41 publications

(49 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unaffected by exercise, this decrease is the first observation of impaired cardiovascular function in SUR2 mutant mice. Male SUR2 mutant mice were previously reported to have cardiac hypertrophy, presumably because of baseline hypertension, and this finding was confirmed here in sedentary female SUR2 mutant mice (22). Kir6.2-null mice also display cardiac hypertrophy, reduced cardiac function, and reduced cardiac output, but only after exercise and not in sedentary mice (15).…”

Section: Discussionsupporting

confidence: 87%

“…Further, Kir6.2 mutant mice have impaired cardiovascular responses to acute and chronic stress, while we did not detect similar findings in SUR2 mutant mice (22,27). SUR2 mutant mice, unlike Kir6.2-null mice, have cardioprotection to acute stress.…”

Section: Perspectives and Significancecontrasting

confidence: 86%

“…SUR2 mutant mice also demonstrate cardioprotection when faced with acute adrenergic stress and ischemia. Taken together, these data suggest that the mild reduction in cardiac function may have limited global effects (22). Of note, Pu et al (20) recently described the existence of additional SUR2 splice variants whose expression is retained in SUR2 mutant mice.…”

Section: Discussionmentioning

confidence: 94%

See 2 more Smart Citations

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Stoller

Pytel²,

Katz³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

EM. Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice. Am J Physiol Regul Integr Comp Physiol 297: R1144 -R1153, 2009. First published August 12, 2009 doi:10.1152/ajpregu.00081.2009.-By sensing intracellular energy levels, ATP-sensitive potassium (K ATP) channels help regulate vascular tone, glucose metabolism, and cardioprotection. SUR2 mutant mice lack full-length K ATP channels in striated and smooth muscle and display a complex phenotype of hypertension and coronary vasospasm. SUR2 mutant mice also display baseline cardioprotection and can withstand acute sympathetic stress better than normal mice. We now studied response to a form of chronic stress, namely that induced by 4 wk of daily exercise on SUR2 mutant mice. Control mice increased exercise capacity by 400% over the training period, while SUR2 mutant mice showed little increase in exercise capacity. Unexercised SUR2 mutant showed necrotic and regenerating fibers in multiple muscle skeletal muscles, including quadriceps, tibialis anterior, and diaphragm muscles. Unlike exercised control animals, SUR2 mutant mice did not lose weight, presumably due to less overall exertion. Unexercised SUR2 mutant mice showed a trend of mildly reduced cardiac function, measured by fractional shortening, (46 Ϯ 4% vs. 57 Ϯ 7% for SUR2 mutant and control, respectively), and this decrease was not exacerbated by chronic exercise exposure. Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 K ATP channels in mice.K ATP channel; sulfonylurea receptor; SUR2; skeletal myopathy; exercise intolerance THE MECHANISMS THAT UNDERLIE the beneficial effects of regular exercise on metabolism and endurance are incompletely understood. ATP-sensitive potassium channels (K ATP channels) are found in muscle and the cardiovascular system and serve as cellular energy sensors. K ATP channels include a regulatory subunit, sulfonylurea receptor (SUR) 1 or 2, and a poreforming potassium channel, Kir6.1 or 6.2. Genetic deletion of the gene encoding Kir6.2 affects K ATP channels in the pancreas, heart, and skeletal muscle due to the lack of the poreforming subunit of K ATP channels (18). Two previous studies have investigated the role of K ATP channels in adaptation to chronic stress and exercise, and both demonstrated an impaired response in Kir6.2-null mice (15,24). Although defects in skeletal muscle and cardiovascular function were reported, the role of K ATP channel involvement is complicated by the ability of Kir6.2 to couple with either sulfonylurea receptor 1 (SUR1) or 2 (SUR2).In the heart, K ATP channels play critical roles during periods of sympathetic stress and protect the heart against ischemia (16,23,27). Kir6.2-null mice stressed with 21 days of experimental hypertension had significantly increased mortality compared with control mice (14). Cardiac function was impaired at baseline and after dobutamine exposure, and hypertensive Kir6.2-null mice developed ...

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Perspectives and Significancecontrasting

confidence: 86%

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Stoller

Pytel²,

Katz³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

show abstract

“…Such a pattern is common in the cardioprotection field; for example, ablation of STAT3 abolishes protection by IPC while having no impact on baseline I/R injury (29,40). It is also notable that genetic ablation of SUR2 increases resistance to I/R injury (30), but this may be due to expression of short-form SUR2 splice variants in the SUR2 Ϫ/Ϫ knockout mouse, which are thought to independently mediate cardioprotection (25,41).…”

Section: Discussionmentioning

confidence: 99%

Kir6.2 is not the mitochondrial K_ATP channel but is required for cardioprotection by ischemic preconditioning

Wojtovich

Urciuoli

Chatterjee

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Wojtovich AP, Urciuoli WR, Chatterjee S, Fisher AB, Nehrke K, Brookes PS. Kir6.2 is not the mitochondrial K ATP channel but is required for cardioprotection by ischemic preconditioning. Am J Physiol Heart Circ Physiol 304: H1439 -H1445, 2013. First published April 12, 2013 doi:10.1152/ajpheart.00972.2012.-ATP-sensitive K ϩ (KATP) channels that contain K ϩ inward rectifier subunits of the 6.2 isotype (Kir6.2) are important regulators of the cardiac response to ischemia-reperfusion (I/R) injury. Opening of these channels is implicated in the cardioprotective mechanism of ischemic preconditioning (IPC), but debate surrounds the contribution of surface KATP (sKATP) versus mitochondrial KATP (mKATP) channels. While responses to I/R injury and IPC have been examined in Kir6.2 Ϫ/Ϫ mice before, breeding methods and other technical obstacles may have confounded interpretations. The aim of this study was to elucidate the role of Kir6.2 in cardioprotection and mKATP activity, using conventionally bred Kir6.2 Ϫ/Ϫ mice with wild-type littermates as controls. We found that perfused hearts from Kir6.2 Ϫ/Ϫ mice exhibited a normal baseline response to I/R injury, were not protected by IPC, and showed a blunted response to the IPC mimetic drug diazoxide. These data suggest that the loss of IPC in Kir6.2 Ϫ/Ϫ hearts is not due to an underlying difference in I/R sensitivity. Furthermore, mKATP channel activity was identical in cardiac mitochondria isolated from wild-type versus Kir6.2 Ϫ/Ϫ mice, suggesting no role for Kir6.2 in the mKATP. Collectively, these data indicate that Kir6.2 is required for the full response to IPC or diazoxide but is not involved in mKATP formation. mitochondria; ischemic preconditioning; K ATP channel; diazoxide THE HEART AND OTHER ORGANS can be protected against ischemiareperfusion (I/R) injury via ischemic preconditioning (IPC), wherein short periods of I/R can engage protective signaling pathways to reduce the impact of a prolonged ischemic event (23). The protective effects of IPC can be mimicked by openers of ATP-sensitive potassium (K ATP ) channels. Since changes in cardiomyocyte bioenergetics are known to occur during IPC (11), the metabolic-sensing role of these channels has driven interest in their potential role in cardioprotective signaling (13,24).K ATP channels comprise octamers of four inward-rectifying potassium channel subunits (Kir6.1 or -6.2) and four sulfonylurea receptors 1, 2A, or 2B (SUR1, -2A, or -2B), with different Kir/SUR combinations giving rise to unique cellular roles, locations, and pharmacological profiles (13). For example, the cardiac surface K ATP (sK ATP ) is Kir6.2/SUR2A. It plays a role in cardiomyocyte volume regulation and stress responses (28) and is activated by cromakalim but not diazoxide (DZX) (11,33,42). In contrast, the pancreatic sK ATP is Kir6.2/SUR1, which plays a role in insulin secretion and is activated by DZX but not cromakalim (13).Despite there being no effect of DZX on cardiac sK ATP channels (4, 9), DZX is known to mimic IPC and protect the heart a...

show abstract

“…Similar to the Kir6.1 Ϫ/Ϫ mice, these mice are hypertensive and exhibit spontaneous coronary vasospasms (115). The SUR2 Ϫ/Ϫ mice are paradoxically protected against ischemia (762). The protection may be due to spontaneous coronary vasospasms that occur in the SUR2 Ϫ/Ϫ mouse hearts that may cause short bursts of ischemia (similar to ischemic preconditioning).…”

Section: Sur2mentioning

confidence: 99%

K_ATPChannels in the Cardiovascular System

Foster

Coetzee

2016

Physiological Reviews

204

237

View full text Add to dashboard Cite

KATP channels are integral to the functions of many cells and tissues. The use of electrophysiological methods has allowed for a detailed characterization of KATP channels in terms of their biophysical properties, nucleotide sensitivities, and modification by pharmacological compounds. However, even though they were first described almost 25 years ago (Noma 1983, Trube and Hescheler 1984), the physiological and pathophysiological roles of these channels, and their regulation by complex biological systems, are only now emerging for many tissues. Even in tissues where their roles have been best defined, there are still many unanswered questions. This review aims to summarize the properties, molecular composition, and pharmacology of KATP channels in various cardiovascular components (atria, specialized conduction system, ventricles, smooth muscle, endothelium, and mitochondria). We will summarize the lessons learned from available genetic mouse models and address the known roles of KATP channels in cardiovascular pathologies and how genetic variation in KATP channel genes contribute to human disease.

show abstract

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

Cited by 41 publications

References 40 publications

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Kir6.2 is not the mitochondrial K_ATP channel but is required for cardioprotection by ischemic preconditioning

K_ATPChannels in the Cardiovascular System

Contact Info

Product

Resources

About

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

Cited by 41 publications

References 40 publications

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Kir6.2 is not the mitochondrial KATP channel but is required for cardioprotection by ischemic preconditioning

KATPChannels in the Cardiovascular System

Contact Info

Product

Resources

About

Kir6.2 is not the mitochondrial K_ATP channel but is required for cardioprotection by ischemic preconditioning

K_ATPChannels in the Cardiovascular System