Hypertension in β-Adducin–Deficient Mice

Abstract

Abstract-Polymorphic variants of the cytoskeletal protein adducin have been associated with hypertension in humans and rats. However, the direct role of this protein in modulating arterial blood pressure has never been demonstrated. To assess the effect of ␤-adducin on blood pressure, a ␤-adducin-deficient mouse strain (Ϫ/Ϫ) was studied and compared with wild-type controls (ϩ/ϩ). Aortic blood pressure was measured in nonanesthetized, freely moving animals with the use of telemetry implants. It is important to note that these mice have at least 98% of C57Bl/6 genetic background, with the only difference from wild-type animals being the ␤-adducin mutation. We found statistically significant higher levels of systolic blood pressure (mm Hg) (meanϮSE values: Ϫ/Ϫ: 126.94Ϯ1.14, nϭ5; ϩ/ϩ: 108.06Ϯ2.34, nϭ6; PՅ0.0001), diastolic blood pressure (Ϫ/Ϫ: 83.54Ϯ1.07; ϩ/ϩ: 74.87Ϯ2.23; PՅ0.005), and pulse blood pressure (Ϫ/Ϫ: 43.32Ϯ1.10; ϩ/ϩ: 33.19Ϯ1.96; PՅ0.001) in ␤-adducin-deficient mice. Western blot analysis showed that as a result of the introduced genetic modification, ␤-adducin was not present in heart protein extracts from Ϫ/Ϫ mice. Consequently, this deficiency produced a sharp decrease of ␣-adducin and a lesser reduction in ␥-adducin levels. However, we found neither cardiac remodeling nor modification of the heart function in these animals. This is the first report showing direct evidence that hypertension is triggered by a mutation in the adducin gene family. Key Words: hypertension, genetic Ⅲ adducin Ⅲ mice, knockout Ⅲ echocardiography Ⅲ cytoskeleton Ⅲ telemetry Ⅲ electrocardiography T he adducin protein family is composed of 3 members encoded by closely related genes: ␣-, ␤-, and ␥-adducin. 1,2 The ␣ and ␤ subunits, but not the ␥ subunit, are found in membrane cytoskeletons of human erythrocytes at the actin-spectrin junctions as a mixture of heterodimers and heterotetramers. Combinations of ␣/␤ and ␣/␥ oligomers are found in the actin cytoskeleton at cell-cell contact sites in other cells. 2,3 Adducin, an unexpected cytoskeletal player as blood pressure (BP) modulator, has been the subject of several association studies that attempted to link adducin variants to hypertension. Since the publication of the first positive association of adducin polymorphism with human hypertension, 4 contradictory results have appeared in the literature. In fact, the human ␣-adducin gene polymorphism (G460W) has been found to be significantly associated with hypertension and salt sensitivity in certain patient groups, 4 -8 although this observation was not confirmed by other groups. 9 -14 The attention to adducin in hypertension was originally drawn by a rat model (Milan hypertensive strain [MHS]), after our characterization of the ␣-and ␤-adducin-specific variants associated with high BP levels. 15 These mutated adducins lead to a higher level of filamentous actin, enhanced actin bundling in cell-free systems, and increased Na-K pump activity when transfected into kidney epithelial cells. 16 However, in both humans and rats, there...

Decrease in Hypothalamic Gamma Adducin in Rat Models of Hypertension

“…21 The antibody showed no cross-reactivity to ␣-or ␤-adducins. 21,22 It recognizes two protein bands of 120 kDa and 105 kDa, which is consistent with our previous data 6 and those of others. 21,22 Both 120-kDa and 105-kDa bands were used to represent total ␥-adducin levels for normalization with tubulin.…”

Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification

“…Mouse ECG changes in response to myocardial ischemia are comparable to those observed in rats, showing R wave enlargement and ST-segment elevation (219). Until recently, the view (17,18,60,88,108,112,129,131,132,138,139,183) References are given for mouse data only. For human data, a normal range is indicated.…”

“…So far, only a few reports have been published (17,18,60,108,129,138,139,183). After the implantation of the pressure sensor, blood pressure and heart rates (HRs) are slightly elevated for 4-5 days (17).…”

Applications of Telemetry in Small Laboratory Animals for Studying Cardiovascular Diseases

“…For example, telemetry has been used to examine hypertension, heart rate variability and baroreflex sensitivity in angiotensin-2-dirupted mice (Gross et al, 2000), hypertension in beta-adducin-deficient mice (Marro et al, 2000), ]circadian rhythm effects on blood pressure in eNOS-knockout mice (Van Vliet et al, 2003), menopause-associated hypertension in follitropin receptor knockout mice (Javeshghani et al, 2003), hypertensive response to acute stress in interleukin-6 knockout mice (Lee et al, 2004), hypertension in D4 dopamine receptor-deficient mice (Bek et al, 2006), endothelial dysfunction and elevated blood pressure in MAS gene-deleted mice (Xu et al, 2008), and so on. We recently published an article where we associated virus-mediated gene transfer to the central nervous system, blood pressure recordings using telemetry, and in vivo bioluminescence technology for longitudinal tracking the expression of the redox-regulated activation of activator protein-1 (AP-1), a nuclear transcriptional factor, during the development of renovascular hypertension in mice (Burmeister et al, 2011).…”