Calofolic Acid‑A from Calophyllum scriblitifolium Bark Has Vasorelaxant Activity via Indirect PKA Activation Caused by PI‑3 Kinase Inhibition in Rat Vascular Smooth Muscle Cells

Previously, we isolated 2R,3S,15R-calofolic acids (CAs) from Calophyllum scriblitifolium bark, which showed vasorelaxant activity on phenylephrine (PE)-precontracted rat aortic rings. Although the effect was suggested to be induced via an extracellular Ca2+-independent manner and mainly acts on vasc...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2022-09, Vol.85 (9), p.2192-2198
Main Authors: Kaneda, Toshio, Ifadotunnikmah, Farida, Nugroho, Alfarius Eko, Koshikawa, Sae, Tadahiro, Sasaki, Hirasawa, Yusuke, Morita, Hiroshi
Format: Article
Language:English
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Summary:Previously, we isolated 2R,3S,15R-calofolic acids (CAs) from Calophyllum scriblitifolium bark, which showed vasorelaxant activity on phenylephrine (PE)-precontracted rat aortic rings. Although the effect was suggested to be induced via an extracellular Ca2+-independent manner and mainly acts on vascular smooth muscle, the exact mechanism of action of CAs remained unclear. Thus, this study investigated the detailed mechanism of calofolic acid-A (CA-A) induced vasorelaxation in an aortic ring specimen using rat vascular smooth muscle cells (VSMCs). The levels of PE-induced phosphorylation on MLC Ser19 decreased in VSMCs pretreated with CA-A. CA-A also decreased the phosphorylation of MYPT1 Thr696 and MYPT1 Thr853. On the other hand, CA-A increased the PE-induced phosphorylation of MYPT1 Ser695 and MYPT1 Ser668, which are reported to be phosphorylated by a cAMP-dependent protein kinase (PKA). CA-A slightly increased PKA substrate phosphorylation in a concentration-dependent manner. Furthermore, CA-A enhanced isoproterenol (ISO)-induced cAMP accumulation and PKA substrate phosphorylation. Treatment with PI-3 kinase (PI3K) inhibitor, LY294002, enhanced ISO-induced cAMP accumulation and PKA substrate phosphorylation in the same manner as CA-A treatment. Furthermore, CA-A was found to directly inhibit PI3K enzyme activity in a dose-dependent manner. Taken together, the present study indicated that CA-A induces vasorelaxation through an indirectly activated PKA-MYPT1 pathway caused by inhibition of PI3K activity.
ISSN:0163-3864
1520-6025
DOI:10.1021/acs.jnatprod.2c00502