Background Cardiovascular disease is the leading cause of death among diabetics. Vitamin D deficiency is associated with increased risk of cardiovascular disease in this population. To determine the mechanism by which vitamin D deficiency mediates accelerated cardiovascular disease in patients with diabetes, we investigated the effects of active vitamin D on macrophage cholesterol deposition. Methods and Results We obtained macrophages from 76 obese, diabetic, hypertensive patients with vitamin D deficiency (25-hydroxyvitamin D < 80 nmol/L)(group A) and four control groups: obese, diabetic, hypertensive patients with normal vitamin D (group B, n=15), obese, non-diabetic, hypertensive patients with vitamin D deficiency (group C, n=25), and non-obese, non-diabetic, non-hypertensive patients with vitamin D deficiency (group D, n=10) or sufficiency (group E, n=10). The same patient’s macrophages from all groups were cultured in vitamin D-deficient or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH)2D3 suppressed foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake in diabetics only. Conversely, deletion of the vitamin D receptor in macrophages from diabetic patients accelerated foam-cell formation induced by modified LDL. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARγ expression, suppressed CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1expression, and prevented oxLDL and AcLDL-derived cholesterol uptake. Conclusion These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam-cell formation and accelerated cardiovascular disease in diabetics.

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These results suggest GPx3 deficiency is a substantive contributing factor to the development of kidney disease-induced cardiac disease.

Background-Angioplasty and stent delivery are performed to treat atherosclerotic vascular disease but often cause deleterious neointimal lesion formation. Previously, growth factor receptor-bound protein 2 (Grb2), an intracellular linker protein, was shown to be essential for neointima formation and for p38 mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (SMCs). In this study, the role of vascular SMC p38␣ MAPK in neointimal development was examined. Methods and Results-Compound transgenic mice were generated with doxycycline-inducible SMC-specific expression of dominant-negative p38␣ MAPK (DN-p38␣). Doxycycline treatment resulted in the expression of DN-p38␣ mRNA and protein in transgenic arteries. Doxycycline-treated compound transgenic mice were resistant to neointima formation 21 days after carotid injury and showed reduced arterial p38 MAPK activation. To explore the mechanism by which p38␣ MAPK promotes neointima formation, an in vitro SMC culture system was used. Inhibition of p38␣ MAPK in cultured SMCs by treatment with SB202190 or small interfering RNA blocked platelet-derived growth factor-induced SMC proliferation, DNA replication, phosphorylation of the retinoblastoma protein, and induction of minichromosome maintenance protein 6. Conclusions-SMC p38␣ MAPK activation is required for neointima formation, perhaps because of its ability to promote retinoblastoma protein phosphorylation and minichromosome maintenance protein 6 expression. (Circulation. 2008; 118:658-666.)

Objective— Grb2 is a ubiquitously expressed linker protein that couples growth factor receptor activation to downstream mitogen-activated protein kinase (MAPK) cascades. Macrophage proliferation and uptake of modified lipoproteins are critical components of atherogenesis which require MAPK activation. However, the precise role of upstream signaling factors and the interrelationship of various MAPK cascades in the pathogenesis of atherosclerosis remains uncertain. Complete deletion of Grb2 in mice results in early embryonic lethality. However, Grb2 heterozygous mice appear normal at birth. To test the role of the Grb2 adapter protein in atherosclerotic lesion formation, we generated Grb2 +/− mice in the apoE −/− genetic background. Methods and Results— Grb2 +/− apoE −/− and apoE −/− mice exhibited similar body weight and serum lipid profiles. However, Grb2 +/− apoE −/− mice on a Western diet had reduced lesion formation compared with apoE −/− mice by aortic sinus and en face assays. Transplantation of apoE −/− mice with Grb2 +/− apoE −/− or apoE −/− bone marrow indicated that Grb2 haploinsufficiency in blood-borne cells confers resistance to Western diet–induced atherosclerosis. Cell culture experiments with bone marrow–derived macrophages showed that Grb2 is required for oxidized low density lipoprotein (oxLDL)-induced MAPK activation and foam cell formation. Conclusions— Grb2 is required for atherosclerotic lesion formation and uptake of oxidized LDL by macrophages.