SUMMARY Resting mitochondrial matrix Ca2+ is maintained through a MICU1-established threshold inhibition of MCU activity. It is not known how MICU1 interacts with MCU to establish this Ca2+ threshold for mitochondrial Ca2+ uptake and MCU activity. Here, we show that MICU1 localizes to the mitochondrial matrix side of the inner mitochondrial membrane and MICU1/MCU binding is determined by a MICU1 N-terminal polybasic domain and two interacting coiled-coil domains of MCU. Further investigation reveals MICU1 forms homo-oligomers, and this oligomerization is independent of the polybasic region. However the polybasic region confers MICU1 oligomeric binding to MCU and controls mitochondrial Ca2+ current (IMCU). Moreover, MICU1 EF-hands regulate MCU channel activity but do not determine MCU binding. Loss of MICU1 promotes MCU activation leading to oxidative burden and a halt to cell migration. These studies establish a molecular mechanism for MICU1 control of MCU-mediated mitochondrial Ca2+ accumulation, and dysregulation of this mechanism likely enhances vascular dysfunction.

Background:The interplay between dyslipidemia-induced inflammation and angiogenesis remains poorly understood. Results: Inhibition of caspase-1 improves VEGFR-2 signaling, tube formation, and blood perfusion in ischemic tissues. Conclusion:The suppression of caspase-1 improves angiogenesis and ischemia prognosis. Significance: Caspase-1 suppression is a novel therapeutic target for improvement of angiogenesis and ischemia under inflammatory environments.

To determine whether caspase-1 is critical in chronic kidney disease (CKD)-mediated arterial neointimal hyperplasia (NH), we utilized caspase−/− mice and induced NH in carotid artery in a CKD environment, and uremic sera-stimulated human vascular smooth muscle cells (VSMC). We made the following findings: (1) Caspase-1 inhibition corrected uremic sera-mediated downregulation of VSMC contractile markers, (2) CKD-promoted NH was attenuated in caspase−/− mice, (3) CKD-mediated downregulation of contractile markers was rescued in caspase null mice, and (4) expression of VSMC migration molecule αvβ3 integrin was reduced in caspase−/− tissues. Our results suggested that caspase-1 pathway senses CKD metabolic danger signals. Further, CKD-mediated increase of contractile markers in VSMC and increased expression of VSMC migration molecule αvβ3 integrin in NH formation were caspase-1 dependent. Therefore, caspase-1 is a novel therapeutic target for the suppression of CKD-promoted NH.

Although permissive hypoventilation leads to respiratory acidosis, it results in less hemodynamic suppression and better perfusion of vital organs. In severely injured penetrating trauma patients, consideration should be given to immediate transportation without PPV.

We recently showed that insulin increased ER stress in human adipose tissue. The effect of insulin resistance on ER stress is not known. It could be decreased, unchanged, or increased, depending on whether insulin regulates ER stress via the metabolic/phosphoinositide 3-kinase (PI3K) or alternate signaling pathways. To address this question, we examined effects of lipid-induced insulin resistance on insulin stimulation of ER stress. mRNAs of several ER stress markers were determined in fat biopsies obtained before and after 8-h hyperglycemic-hyperinsulinemic clamping in 13 normal subjects and in 6 chronically insulin-resistant patients with type 2 diabetes mellitus (T2DM). In normal subjects, hyperglycemia-hyperinsulinemia increased after/before mRNA ratios of several ER stress markers (determined by ER stress pathway array and by individual RT-PCR). Lipid infusion was associated with inhibition of the PI3K insulin-signaling pathway and with a decrease of hyperinsulinemia-induced ER stress responses. In chronically insulin-resistant patients with T2DM, hyperglycemic-hyperinsulinemia did not increase ER stress response marker mRNAs. In summary, insulin resistance, either produced by lipid infusions in normal subjects or chronically present in T2DM patients, was associated with decreased hyperinsulinemia-induced ER stress responses. This suggests, but does not prove, that these two phenomena were causally related.

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Therapeutic/care management study, level II.

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