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Arginase II Activity Regulates Cytosolic Ca2+ Level in a P32-Dependent

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Arginase II Activity Regulates Cytosolic Ca2+ Level in a P32-Dependent Koo et al. Experimental & Molecular Medicine (2019) 51:60 https://doi.org/10.1038/s12276-019-0262-y Experimental & Molecular Medicine ARTICLE Open Access Arginase II activity regulates cytosolic Ca2+ level in a p32-dependent manner that contributes to Ca2+-dependent vasoconstriction in native low-density lipoprotein-stimulated vascular smooth muscle cells Bon-hyeock Koo1, Dongeui Hong2, Hyeon Don Hong2, Hyun Kyo Lim2,KwangLaeHoe3, Moo-Ho Won4, YoungMyeongKim5,DanE.Berkowitz6 and Sungwoo Ryoo1 Abstract Although arginase II (ArgII) is abundant in mitochondria, Ca2+-accumulating organelles, the relationship between ArgII activity and Ca2+ translocation into mitochondria and the regulation of cytosolic Ca2+ signaling are completely unknown. We investigated the effects of ArgII activity on mitochondrial Ca2+ uptake through mitochondrial p32 protein (p32m) and on CaMKII-dependent vascular smooth muscle cell (VSMC) contraction. 2+ Native low-density lipoprotein stimulation induced an increase in [Ca ]m as measured by CoCl2-quenched 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; calcein-AM fluorescence, which was prevented by Arg inhibition in hAoSMCs and reduced in mAoSMCs from ArgII−/− mice. Conversely, [Ca2+]c analyzed with Fluo-4 AM was increased by Arg inhibition and ArgII gene knockout. The increased [Ca2+]c resulted in CaMKII and MLC 20 phosphorylation, which was associated with enhanced vasoconstriction activity to phenylephrine (PE) in the vascular tension assay. Cy5-tagged siRNA against mitochondrial p32 mRNA (sip32m) abolished mitochondrial Ca2+ uptake and induced activation of CaMKII. Spermine, a polyamine, induced mitochondrial Ca2+ uptake and dephosphorylation of CaMKII and was completely inhibited by sip32m incubation. In mAoSMCs from ApoE-null mice fed a high-cholesterol diet (ApoE−/− +HCD), Arg activity was increased, and spermine concentration was higher than that of wild-type mice. Furthermore, [Ca2+]m and p32m levels were elevated, and CaMKII phosphorylation was reduced in mAoSMCs from ApoE−/− +HCD. In vascular tension experiments, an attenuated response to vasoconstrictors in de-endothelialized aorta from ApoE−/− +HCD was recovered by incubation of sip32m. ArgII activity-dependent production of spermine augments Ca2+ transition from the cytosol to the mitochondria in a p32m-dependent manner and regulates CaMKII-dependent constriction in VSMCs. Introduction Arginase hydrolyzes L-arginine to urea and L-ornithine, Correspondence: Sungwoo Ryoo ([email protected]) a precursor for polyamines, including spermine, spermi- 1Department of Biology, School of Medicine, Kangwon National University, dine, and putrescine. Two isoforms of arginase are found Chuncheon 24341, South Korea 2 in a variety of cells and may be expressed in species- and Department of Anesthesiology and Pain Medicine, Yonsei University Wonju 1–5 College of Medicine, Wonju 26426, South Korea tissue-specific manners . Arginase I (ArgI) is found in Full list of author information is available at the end of the article. © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Koo et al. Experimental & Molecular Medicine (2019) 51:60 Page 2 of 12 the cytosol, and arginase II (ArgII) is targeted to the Materials and methods mitochondria. Although ArgI can stimulate proliferation Materials through a polyamine-dependent mechanism in aortic We purchased 2(S)-amino-6-boronohexanoic acid smooth muscle cells6, the mechanism underlying the role (ABH) from Calbiochem (La Jolla, CA, USA). Antibodies of ArgII in mitochondrial function is yet unknown. We against p-CaMKII (Cat. No. 12716), CaMKII (Cat. No. previously demonstrated that ArgII played an important 3362), MLC20 (Cat. No. 3672), and p-MLC20 (Cat. No. + role in the regulation of mitochondrial Ca2 concentra- 3674) were purchased from Cell Signaling Technology tion in native low-density lipoprotein (nLDL)-treated (Danvers, MA, USA). Arginase II (sc-20151), eNOS (sc- hAoSMCs, although we did not define the target protein7. 645), HSP60 (sc-1052), and α-actin (sc-56459) antibodies Together with the endoplasmic reticulum, the mito- were purchased from Santa Cruz Biotechnology (Santa + chondria play a critical role as a Ca2 -handling organelle Cruz, CA, USA). p32 antiserum was obtained from + in cells, and mitochondrial Ca2 influx from the cytosol Abcam, Co. (Cat. No. AB2991, Cambridge, MA). siRNA affects cellular physiology and pathophysiology through against arginase II (siArgII, sc‐29729) and scramble RNA contributions to the spatial and temporal profiles of (scmRNA, sc‐37007) were purchased from Santa Cruz + intracellular Ca2 signaling. Biotechnology. All reagents were purchased from Sigma + Calmodulin contains four EF-hand Ca2 binding sites (St. Louis, MO, USA) unless otherwise stated. + and is a major Ca2 sensor and regulatory protein. In vascular smooth muscle cells (VSMCs), increased cyto- Isolation of nLDL and cell culture + + − solic concentration of Ca2 ([Ca2 ]c) activates the mul- The nLDL (density 1.019–1.063 g ml 1) was prepared + tifunctional Ca2 /calmodulin-dependent kinase II from the plasma of normocholesterolemic subjects by (CaMKII)8. The activated CaMKII provokes vascular differential ultracentrifugation as previously described7. smooth muscle cell (VSMC) contraction through inter- Isolated nLDL did not exhibit oxidative modification actions with myosin light chain kinase (MLCK), leading to within 3 weeks compared with the oxidation of com- MLC phosphorylation and actin-myosin interaction9,10. mercial nLDL and oxidized LDL from Intracel (Frederick, + Furthermore, increased levels of intracellular Ca2 may MD, USA), as determined by thiobarbiturate-reactive function as a second messenger to activate other signaling substance assays using malondialdehyde as a standard. – molecules11 13. Human aortic smooth muscle cells (hAoSMCs) from Initially, p32 was characterized as a pre-mRNA splicing four different batches were purchased from Lonza, Co. factor SF-2 associated protein14, as hyaluronan-binding (Allendale, NJ, USA), maintained in medium 231 supple- protein 1 (HABP1), as receptor for globular head mented with SMGS (Cascade Biologics, Portland, OR, domains complement 1q (gC1qR), or as complement 1q USA) according to the manufacturer’s protocol and binding protein (C1qbp)15. Moreover, p32 is a conserved treated with nLDL (final concentration, 100 µg/ml) after eukaryotic protein that exists in multiple subcellular incubation in starvation medium (DMEM, 0.1% FBS, 100 – compartments16 18. However, recent studies have U/ml penicillin, 100 µg/ml streptomycin) for 24 h. demonstrated that p32 is primarily targeted to the mAoSMCs of at least eight different batches were isolated mitochondria because the 73 N-terminal amino acids from the thoracic and upper parts of the abdominal aorta contain a mitochondrial localization sequence19. Mito- of 10-week-old male mice (C57BL/6) as previously chondrial p32 protein has been studied previously in described23 with minor modifications. Briefly, the stripped cancer development in the context of mitochondrion aorta was prepared from the anesthetized mice and cut morphology20, the maintenance of oxidative phosphor- into 2-mm pieces, which were treated with type II col- ylation21, and ARF-induced apoptosis22. However, the lagenase (1 mg/ml, Invitrogen, Carlsbad, CA, USA) for primary function of p32 in the mitochondrion is yet 1 hr to remove the endothelial cells. The de- unknown. endothelialized aortic pieces were incubated with cul- Although arginase activity in VSMCs provokes cell ture medium on gelatin (0.1%)-coated culture dishes for proliferation in a polyamine-dependent manner6, the approximately 10 days. The cells were cultured in DMEM protein regulated by arginase activity and its function in supplemented with 10% FBS, 100 U/ml penicillin, the mitochondrion are not yet known. To determine the 100 µg/ml streptomycin, 8 mM HEPES, and 2 mM gluta- physiological contribution of ArgII activity to vasocon- mine at 37 °C in a humidified 5% CO2 incubator. Before striction in VSMCs from humans and mice, we investi- all experiments, isolated mAoSMCs at passage numbers + + gated how ArgII activity modulates [Ca2 ]c and [Ca2 ]m 1–3 were maintained for 24 h in starvation medium to through p32. Furthermore, we tested the underlying maintain their contractile phenotype. mAoSMCs were mechanism of p32-dependent vasoconstriction in de- identified by their ‘spindle-shaped’ pattern and further endothelialized vessels. confirmed by double staining using platelet endothelial Official journal of the Korean Society for Biochemistry and Molecular Biology Koo et al. Experimental & Molecular Medicine (2019)
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