ABSTRACT
OBJECTIVE: Smooth muscle cells contribute significantly to lipid-laden foam cells in atherosclerotic plaques. However, the underlying mechanisms transforming smooth muscle cells into foam cells are poorly understood. The purpose of this study was to gain insight into the molecular mechanisms regulating smooth muscle foam cell formation. APPROACH AND RESULTS: Using human coronary artery smooth muscle cells we found that the transcriptional co-activator MRTFA promotes lipid accumulation via several mechanisms, including direct transcriptional control of LDL receptor, enhanced fluid-phase pinocytosis and reduced lipid efflux. Inhibition of MRTF activity with CCG1423 and CCG203971 significantly reduced lipid accumulation. Furthermore, we demonstrate enhanced MRTFA expression in vascular remodeling of human vessels. CONCLUSIONS: This study demonstrates a novel role for MRTFA as an important regulator of lipid homeostasis in vascular smooth muscle cells. Thus, MRTFA could potentially be a new therapeutic target for inhibition of vascular lipid accumulation.
Subject(s)
Cell Transdifferentiation , Foam Cells/metabolism , Lipid Metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Trans-Activators/metabolism , Coronary Vessels/metabolism , Coronary Vessels/pathology , Foam Cells/pathology , HEK293 Cells , Humans , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/pathology , Neointima , Pinocytosis , Receptors, LDL/genetics , Receptors, LDL/metabolism , Trans-Activators/genetics , Up-Regulation , Vascular RemodelingABSTRACT
BACKGROUND: Primary hyperparathyroidism (pHPT) is caused by single- or multiglandular disease (MGD). Patients with MGD have an increased risk of complications at surgery and for persistence and recurrence after surgery. The study evaluated whether preoperative clinical and biochemical characteristics could predict MGD in patients with pHPT. METHODS: We retrospectively evaluated patients operated 1989-2013 for first-time, non-hereditary pHPT. MGD was defined in patients with more than one pathological gland excised at surgery or with persistent hypercalcemia after the excision of a single pathological parathyroid gland, confirmed by histopathology. Clinical and biochemical variables were compared in patients with single- and multiglandular disease. Logistic regression was used to identify variables predicting MGD, yielding odds ratios (OR) with 95% confidence intervals (CI). RESULTS: There were 707 patients, of which 79 (11%) had MGD. Patients with MGD were more likely to have negative sestamibi scintigraphy than patients with single-gland disease, 15 of 49 (31%) vs. 70 of 402 (17%; p = 0.03), to suffer from diabetes (12 of 74, 16%) vs. 45 out of 626 patients (7.2%; p < 0.01) and had lower preoperative levels of urinary calcium (3.80 vs. 4.44 mmol/L; p = 0.04). Multivariable analysis identified negative scintigraphy (OR 2.42; 95% CI 1.18 to 4.79), diabetes (OR 2.75; 95% CI 1.31 to 4.97) and elevated levels of osteocalcin (OR 3.79, 95% CI: 1.75 to 8.21) as predictors of MGD. CONCLUSION: Negative sestamibi scintigraphy, diabetes and elevated osteocalcin levels were predictors of MGD.
