Increased tolerance to stress in cardiac expressed gain-of-function of adenosine triphosphate-sensitive potassium channel subunit Kir6.1

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• 作者：Matthew C. Henn ; MD^a ; M. Burhan Janjua ; MD^b ; Haixia Zhang ; PhD^c ; Evelyn M. Kanter ; BS^a ; Carol M. Makepeace ; BS^a ; Richard B. Schuessler ; PhD^a ; Colin G. Nichols ; PhD^c ; Jennifer S. Lawton ; MD ; FACS^a ; ^{jlawton4@jhmi.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Potassium channel ; Myocardial stress ; Diazoxide ; Cantu syndrome
• 刊名：Journal of Surgical Research
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：206
• 期：2
• 页码：460-465
• 全文大小：808 K

文摘

The adenosine triphosphate–sensitive potassium (K_ATP) channel opener diazoxide (DZX) prevents myocyte volume derangement and reduced contractility secondary to stress. K_ATP channels are composed of pore-forming (Kir6.1 or Kir6.2) and regulatory (sulfonylurea receptor, SUR1 or SUR2) subunits. Gain of function (GOF) of Kir6.1 subunits has been implicated in cardiac pathology in Cantu syndrome in humans (cardiomegaly, lymphedema, and pericardial effusions). We hypothesized that GOF of Kir6.1 subunits would result in altered myocyte response to stress.

Materials and methods

Isolated cardiac myocytes from wild type (WT) and transgenic Kir6.1GOF mice were exposed to Tyrode's physiologic solution for 20 min, test solution (Tyrode's or stress [hyperkalemic cardioplegia {CPG, known myocyte stress}] +/− K_ATP channel opener DZX), followed by Tyrode's for 20 min. Myocyte volume and contractility were measured and compared.

Results

WT myocytes demonstrated significant swelling in response to stress, but significantly less swelling was seen in Kir6.1GOF myocytes. DZX prevented swelling secondary to CPG in WT but resulted in a nonsignificant reduction in swelling in Kir6.1GOF myocytes. Both WT and Kir6.1GOF myocytes demonstrated a reduction in contractility during stress, although this was only significant in Kir6.1GOF myocytes. DZX was not associated with an improvement in contractility in Kir6.1GOF myocytes following stress.

Conclusions

Similar to previous results in Kir6.1(−/−) myocytes, Kir6.1GOF myocytes demonstrate resistance (less volume derangement) to stress of cardioplegia. Understanding the role of Kir6.1 in myocyte response to stress may aid in the treatment of patients with Cantu syndrome and warrants further investigation.