ABSTRACT
BACKGROUND: Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life-threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity-related metabolic disorders, moving the tissue toward a proinflammatory phenotype. METHODS AND RESULTS: Here we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of ATRAP/Agtrap, which is a specific binding modulator of the angiotensin II type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of ATRAP in the pathophysiology of metabolic disorders, we produced homozygous ATRAP deficient (Agtrap(-/-)) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading, Agtrap(-/-) mice displayed systemic metabolic dysfunction, characterized by an increased accumulation of pad fat, hypertension, dyslipidemia, and insulin resistance, along with adipose tissue inflammation. Conversely, subcutaneous transplantation of donor fat pads overexpressing ATRAP derived from Agtrap transgenic mice to Agtrap(-/-) recipient mice improved the systemic metabolic dysfunction. CONCLUSIONS: These results demonstrate that Agtrap(-/-) mice are an effective model of metabolic disorders with visceral obesity and constitute evidence that ATRAP plays a protective role against insulin resistance, suggesting a new therapeutic target in metabolic disorders. Identification of ATRAP as a novel receptor binding modulator of adipose tissue inflammation not only has cardiovascular significance but may have generalized implication in the regulation of tissue function.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Intra-Abdominal Fat/metabolism , Metabolic Syndrome/metabolism , Obesity, Abdominal/metabolism , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Adiposity , Adult , Animals , Biomarkers/blood , Blood Pressure , Case-Control Studies , Diet, High-Fat , Disease Models, Animal , Dyslipidemias/metabolism , Dyslipidemias/physiopathology , Female , Genotype , Homozygote , Humans , Hypertension/metabolism , Hypertension/physiopathology , Hypertrophy , Insulin Resistance , Intra-Abdominal Fat/pathology , Intra-Abdominal Fat/physiopathology , Intra-Abdominal Fat/transplantation , Male , Metabolic Syndrome/genetics , Metabolic Syndrome/physiopathology , Metabolic Syndrome/prevention & control , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Middle Aged , Obesity, Abdominal/genetics , Obesity, Abdominal/physiopathology , Panniculitis/metabolism , Panniculitis/physiopathology , Phenotype , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Time Factors , Young AdultABSTRACT
We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na(+)-Ca(2+) exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.
Subject(s)
Blood Pressure/physiology , Hypertension/genetics , Hypertension/physiopathology , Muscle, Smooth, Vascular/physiopathology , Plasma Membrane Calcium-Transporting ATPases/genetics , Animals , Calcium/metabolism , Cells, Cultured , Disease Models, Animal , Femoral Artery/drug effects , Femoral Artery/physiology , Gene Deletion , Homeostasis/physiology , Mice , Mice, Knockout , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Phenylephrine/pharmacology , Plasma Membrane Calcium-Transporting ATPases/deficiency , Vasoconstriction/drug effects , Vasoconstriction/physiologyABSTRACT
Dialysis-related amyloidosis (DRA) is one of the major complications often seen in long-term dialysis patients, and is one of the factors that decreases quality of life. ß2-microglobulin (ß2-m) is considered to be a major pathogenic factor in dialysis-related amyloidosis. The Lixelle adsorbent column, with various capacities, has been developed to adsorb ß2-m from the circulating blood of patients with dialysis-related amyloidosis. Using a minimum type of ß2-m-adsorbing column (Lixelle S-15), we evaluated its therapeutic efficacy and safety in dialysis patients. Seventeen hemodialysis patients with DRA were treated with the S-15 column for one year. Treatment was performed three times a week in this study. During the study period, pinch strength, visual analog scale for joint pain, and activities of daily living were evaluated every three months, and blood sampling was performed every six months. After one year's treatment with the S-15 column, the ß2-m level decreased from 29.3±9.6mg/L to 24.7±5.1mg/L (P<0.05), and the high sensitive C-reactive protein level decreased from 2996±4380ng/mL to 1292±1774ng/mL. After one year of S-15 column use, pinch strength increased from 5.9±3.0pounds to 7.2±3.2pounds (P<0.05), and the visual analog scale for joint pain and activities of daily living score also improved. Long-term use of the Lixelle S-15 column is safe and effective for improvement of quality of life in chronic dialysis patients. Improvement of chronic inflammation may be one of the mechanisms through which the beneficial effects of the column is effected.