BK channel β1-subunit deficiency exacerbates vascular fibrosis and remodelling but does not promote hypertension in high-fat fed obesity in mice

Abstract

Objective Reduced expression or increased degradation of BK (large conductance Ca2+-activated K+) channel β1-subunits has been associated with increased vascular tone and hypertension in some metabolic diseases. The contribution of BK channel function to control of blood pressure (BP), heart rate (HR) and vascular function/structure was determined in wild-type and BK channel β1-subunit knockout mice fed a high-fat or control diet. Methods and Results After 24 weeks of high-fat diet, wild-type and BK β1-knockout mice were obese, diabetic, but normotensive. High-fat-BK β1-knockout mice had decreased HR while high-fat-wild-type mice had increased HR compared with mice on the control diet. Ganglion blockade caused a greater fall in BP and HR in high-fat mice than in mice on the control diet. β1-adrenergic receptor blockade reduced BP and HR equally in all groups. α1-adrenergic receptor blockade decreased BP in high-fat-BK β1-knockout mice only. Echocardiographic evaluation revealed left ventricular hypertrophy in high-fat-BK β1-knockout mice. Although under anesthesia, mice on a high-fat had higher absolute stroke volume and cardiac output, these measures were similar to control mice when adjusted for body weight. Mesenteric arteries from high-fat-BK β1-knockout mice had higher norepinephrine reactivity, greater wall thickness and collagen accumulation than high-fat-wild-type mesenteric arteries. Compared with control-wild-type mesenteric arteries, high-fat-wild-type mesenteric arteries had blunted contractile responses to a BK channel blocker, although BK α-subunit (protein) and β1-subunit (mRNA) expression were unchanged. Conclusions BK channel deficiency promotes increased sympathetic control of blood pressure, and vascular dysfunction, remodeling and fibrosis, but does not cause hypertension in high-fat fed mice.

Modulation of BK Channel Function by Auxiliary Beta and Gamma Subunits

“…Studies with knockout mice showed that the presence of the β1 subunit was critical to normal BK channel function in vascular smooth muscle cells (Werner et al, 2007, 2008). One recent report showed that β1 deficiency exacerbated vascular fibrosis and remodeling (Xu et al, 2015). The knockout mice of β4 subunit showed signs of an epileptic phenotype (Brenner et al, 2005), and the β2 knockout mice had an increased tendency toward spontaneous burst firing in the adrenal medullary chromaffin cells (Martinez-Espinosa et al, 2014).…”

Increased Muscle Mass Protects Against Hypertension and Renal Injury in Obesity

“…Male adult mice (19.1±0.8 weeks old) were used for the duration of this experiment. The db/db mouse was selected because it produces a reliable hypertensive response and to avoid the confounding effects of weight loss associated with the impact of myostatin in diet‐induced obesity models 19, 20, 21, 22, 23, 24. To generate animals for this study, myostatin knockout mice were crossed onto the db/db background, as previously described 25.…”

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

“… showed that higher ratio of β1 subunit: α‐subunit in cerebral VSMCs related to that in skeletal muscle may lead to higher Ca +2 sensitivity of BK Ca current in cerebral arteries. It is well known that BK Ca is primarily activated either by an elevation of the [Ca +2 ]i or by membrane depolarization and maintain MP and vascular myogenic tone through negative feedback modulation . Hence, BK Ca affects as a relaxing negative feedback mechanism after agonist‐induced membrane depolarization and extracellular Ca +2 entry in most isolated arteries obtained from animals and humans .…”

“…Impaired β1 subunits inhibited BK Ca activation in cerebral arteries of hypertensive rats, leading to dysfunctional vasodilation . Disruption and knockout of the BK Ca ‐β1 gene ( KCNMB1 ) were associated with elevated blood pressure in mice, and downregulation of the β1 subunit was been reported in hypertensive rats . β1 knockout mice were hypertensive, indicating that uncoupling BK Ca from RyRs by the loss of the β1 subunit alone is sufficient to induce hypertension .…”

“…β1 knockout mice were hypertensive, indicating that uncoupling BK Ca from RyRs by the loss of the β1 subunit alone is sufficient to induce hypertension . It was demonstrated that β1 knockout mice had higher systemic blood pressure than control mice (β1‐subunit gene +) . It has been also reported that expression of the pore‐forming α subunit of BK Ca is increased in cerebral, mesenteric, and coronary arteries, which are microcirculatory beds .…”