The morphological and functional alterations of the cochlea in apolipoprotein E deficient mice

Division of Allergy and Immunology, Departments of Medicine, Molecular Sciences and Otolaryngology and Neuroscience Institute, College of Medicine, VA Medical Center, Memphis, TN 38104, USA.
Hearing Research (Impact Factor: 2.97). 11/2005; 208(1-2):54-67. DOI: 10.1016/j.heares.2005.05.010
Source: PubMed


The relationship between hyperlipidemia and sensorineural hearing loss remains obscure. In this study, we elucidate for the first time the cochlear morphological and auditory alterations and their relationships with hyperlipidemia, atherosclerosis, and endothelial dysfunction in apolipoprotein-E knockout (ApoE-KO) mice. Ten-week-old ApoE-KO mice were fed either atherosclerotic diet (1.25% cholesterol) or normal diet. Wild type mice (C57BL/6J) served as normal controls. Fourteen weeks later, marked hyperlipidemia, atherosclerosis, endothelial dysfunction, and hearing impairment, especially in the high frequencies, had developed in ApoE-KO mice as compared with C57BL/6J mice (P<0.001). A high positive correlation between hearing loss and the extent of atherosclerosis and plasma total cholesterol levels was found. Hearing loss, especially at high frequencies, was detected in all ApoE-KO mice. Hair cell loss mainly at the base turn, thickening of vascular intima, and lumen stenosis of the spiral modiolar artery (SMA) in cochlea were also found; these histological changes were exacerbated by the atherosclerotic diet. Furthermore, endothelial nitric oxide synthase (eNOS) in aortic wall and cochlea was distinctly reduced in ApoE-KO mice. These results demonstrate that hyperlipidemia and atherosclerosis can induce alterations in cochlear morphology and function. The stenosis of SMA, which may cause cochlear ischemia and hypoxia, endothelial dysfunction, and low eNOS activity, may contribute to hearing loss.

4 Reads
  • Source
    • "Atherosclerosis was induced in the aortas of 8‐week‐old ApoE‐knockout male mice on a C57BL/6 background (Jackson Laboratories) by a Western diet containing 21% fat, 0.15% cholesterol, and 19.5% casein for 20 weeks as described previously.16 Atherosclerotic lesions were confirmed by oil red O staining using en face preparation of whole aortas and hematoxylin‐eosin staining of cross‐sections of proximal aortas (aortic sinus, ascending aorta, arch, and thoracic aorta) as shown in our previous publications.17–18 To upregulate the miR‐145 in mouse aortas, 50‐μL solutions of Ad‐miR‐145 (5×1010 pfu/mL) or control Ad‐GFP (5×1010 pfu/mL) were injected via the tail vein. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many microRNAs (miRNAs) are downregulated in proliferative vascular disease. Thus, upregulation of these miRNAs has become a major focus of research activity. However, there is a critical barrier in gene therapy to upregulate some miRNAs such as miR-145 and miR-143 because of their significant downregulation by the unclear endogenous mechanisms under disease conditions. The purpose of this study was to determine the molecular mechanisms responsible for their downregulation and to overcome the therapeutic barrier. In cultured proliferative rat vascular smooth muscle cells (VSMCs) in vitro and in diseased rat and mouse arteries in vivo, we have identified that the impairment of pri-miR-145 into pre-miR-145 is the critical step related to the downregulation of miR-145, in which the PI3-kinase/Akt/p53 pathway is involved. We further identified that the flank sequences of pri-miR-145 are the critical structural components responsible for the aberrant miR-145 expression. Switching of the flank sequence of downregulated miR-145 and miR-143 to the flank sequence of miR-31 confers resistance to their downregulation. The genetically engineered miR-145 (smart miR-145) restored the downregulated miR-145 in proliferative rat VSMCs and in rat carotid arteries with balloon injury and mouse atherosclerotic aortas and demonstrated much better therapeutic effects on the abnormal growth of VSMCs, expression of its target gene, KLF5 expression, VSMC marker gene expression, and vascular neointimal growth. The flank sequences of miR-145 and miR-143 play a critical role in their aberrant expression in VSMCs and vascular walls. The genetically engineered "smart" miRNAs based on their flank sequences may have broadly therapeutic applications for many vascular diseases.
    Full-text · Article · Oct 2013 · Journal of the American Heart Association
  • Source
    • "Animals and treatment Male apoE KO mice with wild-type C57BL/6 were purchased from Japan SLC Incorporation (Tokyo, Japan), which were kept both for 12 weeks on a high-cholesterol diet (1.25% cholesterol, 7.5% cocoa butter, 0.5% sodium cholate, DYET#102068; Dyets Inc., Bethelehem, PA, USA) (Guo et al. 2005). On the 8th week post induction of hyperlipidemia, the mice were intraperitoneally (i.p.) injected with ginseng extracts (100 mg/kg/day) for 4 weeks. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ginsenosides, bioactive compounds of Panax Ginseng C.A. Meyer, are divided into protopanaxadiol (PD) and protopanaxtriol (PT). The aim of this study was to evaluate the protective effects of different PD and PT combination ratios on liver inflammation and apoptosis in hyperlipidemic apo E KO mice. R1 (PD/PT = 1, high Rg1 and Rb1) and R2 (PD/PT = 2, high Re and Rd) extracts were intraperitoneally injected by 100 mg/kg/day at the 8th week. R1 and R2 improved atherogenic indices by increasing HDL and lowering total cholesterol (TC) and triacylglyceride (TG) selectively. R1 decreased lipid peroxides (LPO) level in plasma and liver tissue of hyperlipidemic mice, and R2 lowered plasma malondialdehyde(MDA) level. R1 and R2 not only regulated the expression of cyclooxygenase (COX)-2, IκB-α, phopho-ERK 1/2, and phopho-SAPK/JNK levels but also were significantly effective in blocking apoptotic signals, such as caspase-8, -9, as well as the cleavage of PARP in liver. Different combinational treatment of PD and PT extracts might ameliorate the liver inflammation and apoptosis in hyperlipidemic apo E KO mice, which is atherosclerotic animal model.
    Full-text · Article · Aug 2011 · Genes & Nutrition
  • Source
    • "Previous studies of apolipoproteins in cochlea were restricted to ApoE1 and ApoD, where mice deficient in the former showed a hearing loss and substantial cochlear cell death [5] [25], while ApoD knockouts had normal hearing thresholds [26]. Putative roles include cochlear ionic and oxidative homeostasis [25] [26], a balance that may be connected to ion channels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Owing to the multifaceted functions of the large conductance Ca(2+)-activated K(+) channel (BK), identification of protein-protein interactions is essential in determining BK regulation. A yeast two-hybrid screening of a cochlear cDNA library revealed a BK-ApoA1 interaction. Patch clamp recordings of excised membrane patches from transfected HEK293 cells showed that ApoA1 inhibits the BK alpha-subunit by significantly increasing activation and deactivation times, and shifting half-activation voltage to more positive potentials. Reciprocal coimmunoprecipitations verified the BK-ApoA1 interaction using excised sensory epithelium and ganglia. Additionally, immunocolocalization studies revealed BK and ApoA1 expression in both receptor cells and auditory neurons. These data suggest new avenues of investigation, given the importance of apolipoproteins in neurological diseases.
    Full-text · Article · Aug 2009 · Biochemical and Biophysical Research Communications
Show more