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

Autor: Moo-Ho Won, Young Myeong Kim, Dan E. Berkowitz, Hyun Kyo Lim, Dongeui Hong, Hyeon Hong, Bon-Hyeock Koo, Kwang Lae Hoe, Sungwoo Ryoo
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Experimental and Molecular Medicine, Vol 51, Iss 6, Pp 1-12 (2019)
ISSN: 2092-6413
1226-3613
Popis: 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. Native low-density lipoprotein stimulation induced an increase in [Ca2+]m as measured by CoCl2-quenched 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. Researchers have illuminated how a protein, arginase II (ArgII), is involved in development of vascular diseases such as atherosclerosis, or narrowing of the arteries by plaque deposits. Blood vessel diameter is regulated by layers of muscle; the balance between constriction and relaxation is critical for blood flow and vascular health. Increased ArgII is known to be a factor in arterial disease; however, the details of regulation, and how they relate to plaque deposition, remain poorly understood. Sungwoo Ryoo at Kangwon National University, Chuncheon, South Korea and co-workers investigated how ArgII levels affect arterial constriction and relaxation in mice. Decreasing ArgII restored the muscle cells’ contraction response by preventing excessive calcium accumulation in the cellular powerhouse, mitochondria. These results may aid in developing treatments for one of the leading causes of death worldwide.
Databáze: OpenAIRE
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