Hypotension Due to Kir6.1 Gain-of-Function in Vascular Smooth Muscle

被引:57
作者
Li, Anlong [1 ,3 ]
Knutsen, Russell H. [1 ]
Zhang, Haixia [1 ,3 ]
Osei-Owusu, Patrick [1 ]
Moreno-Dominguez, Alex [3 ]
Harter, Theresa M. [1 ,3 ]
Uchida, Keita [1 ,3 ]
Remedi, Maria S. [1 ,3 ]
Dietrich, Hans H. [2 ]
Bernal-Mizrachi, Carlos [4 ]
Blumer, Kendall J. [1 ]
Mecham, Robert P. [1 ]
Koster, Joseph C. [1 ]
Nichols, Colin G. [1 ,3 ]
机构
[1] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Neurol Surg, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Ctr Invest Membrane Excitabil Dis, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Dept Med, Div Endocrinol, St Louis, MO 63110 USA
来源
JOURNAL OF THE AMERICAN HEART ASSOCIATION | 2013年 / 2卷 / 04期
基金
美国国家卫生研究院;
关键词
hypotension; K-ATP; KCNJ8; mice; transgenic; ABCC9; K-ATP CHANNELS; SENSITIVE POTASSIUM CHANNELS; SULFONYLUREA RECEPTOR; INSULIN-SECRETION; BLOOD-PRESSURE; CANTU SYNDROME; MICE; MUTATIONS; SUBUNIT; HYPERTENSION;
D O I
10.1161/JAHA.113.000365
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-K-ATP channels, assembled from pore-forming (Kir6.1 or Kir6.2) and regulatory (SUR1 or SUR2) subunits, link metabolism to excitability. Loss of Kir6.2 results in hypoglycemia and hyperinsulinemia, whereas loss of Kir6.1 causes Prinzmetal angina-like symptoms in mice. Conversely, overactivity of Kir6.2 induces neonatal diabetes in mice and humans, but consequences of Kir6.1 overactivity are unknown. Methods and Results-We generated transgenic mice expressing wild-type (WT), ATP-insensitive Kir6.1 [Gly343Asp] (GD), and ATP-insensitive Kir6.1 [Gly343Asp,Gln53Arg] (GD-QR) subunits, under Cre-recombinase control. Expression was induced in smooth muscle cells by crossing with smooth muscle myosin heavy chain promoter-driven tamoxifen-inducible Cre-recombinase (SMMHC-Cre-ER) mice. Three weeks after tamoxifen induction, we assessed blood pressure in anesthetized and conscious animals, as well as contractility of mesenteric artery smooth muscle and K-ATP currents in isolated mesenteric artery myocytes. Both systolic and diastolic blood pressures were significantly reduced in GD and GD-QR mice but normal in mice expressing the WT transgene and elevated in Kir6.1 knockout mice as well as in mice expressing dominant-negative Kir6.1 [AAA] in smooth muscle. Contractile response of isolated GD-QR mesenteric arteries was blunted relative to WT controls, but nitroprusside relaxation was unaffected. Basal K-ATP conductance and pinacidil-activated conductance were elevated in GD but not in WT myocytes. Conclusions-K-ATP overactivity in vascular muscle can lead directly to reduced vascular contractility and lower blood pressure. We predict that gain of vascular K-ATP function in humans would lead to a chronic vasodilatory phenotype, as indeed has recently been demonstrated in Cantu syndrome.
引用
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页数:13
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