Cellular Effects of Butyrate on Vascular Smooth Muscle Cells are Mediated through Disparate Actions on Dual Targets, Histone Deacetylase (HDAC) Activity and PI3K/Akt Signaling Network
by
Omana P. Mathew, Kasturi Ranganna *, Joseph Mathew, Meiling Zhu, Zivar Yousefipour, Chelliah Selvam and Shirlette G. Milton
Omana P. Mathew, Kasturi Ranganna *, Joseph Mathew, Meiling Zhu, Zivar Yousefipour, Chelliah Selvam and Shirlette G. Milton
Department of Pharmaceutical and Environmental Health Sciences, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne St, Houston, TX 77004, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(12), 2902; https://doi.org/10.3390/ijms20122902
Received: 22 May 2019 / Revised: 8 June 2019 / Accepted: 11 June 2019 / Published: 14 June 2019
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
Vascular remodeling is a characteristic feature of cardiovascular diseases. Altered cellular processes of vascular smooth muscle cells (VSMCs) is a crucial component in vascular remodeling. Histone deacetylase inhibitor (HDACI), butyrate, arrests VSMC proliferation and promotes cell growth. The objective of the study is to determine the mechanism of butyrate-induced VSMC growth. Using proliferating VSMCs exposed to 5 mM butyrate, immunoblotting studies are performed to determine whether PI3K/Akt pathway that regulates different cellular effects is a target of butyrate-induced VSMC growth. Butyrate inhibits phosphorylation-dependent activation of PI3K, PDK1, and Akt, eliciting differential effects on downstream targets of Akt. Along with previously reported Ser9 phosphorylation-mediated GSK3 inactivation leading to stability, increased expression and accumulation of cyclin D1, and epigenetic histone modifications, inactivation of Akt by butyrate results in: transcriptional activation of FOXO1 and FOXO3 promoting G1 arrest through p21Cip1/Waf1 and p15INK4B upregulation; inactivation of mTOR inhibiting activation of its targets p70S6K and 4E-BP1 impeding protein synthesis; inhibition of caspase 3 cleavage and downregulation of PARP preventing apoptosis. Our findings imply butyrate abrogates Akt activation, causing differential effects on Akt targets promoting convergence of cross-talk between their complimentary actions leading to VSMC growth by arresting proliferation and inhibiting apoptosis through its effect on dual targets, HDAC activity and PI3K/Akt pathway network.
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MDPI and ACS Style
Mathew, O.P.; Ranganna, K.; Mathew, J.; Zhu, M.; Yousefipour, Z.; Selvam, C.; Milton, S.G. Cellular Effects of Butyrate on Vascular Smooth Muscle Cells are Mediated through Disparate Actions on Dual Targets, Histone Deacetylase (HDAC) Activity and PI3K/Akt Signaling Network. Int. J. Mol. Sci. 2019, 20, 2902.
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