Nifedipine Inhibits Vascular Smooth Muscle Cell Dedifferentiation via Downregulation of Akt Signaling

Abstract

Abstract-Calcium is an essential signaling molecule that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and differentiation. Here, we show that the calcium antagonist nifedipine inhibits VSMC dedifferentiation in vitro and in vivo. Differentiated VSMCs cultured on laminin-coated dishes were transferred to laminin-free dishes to induce dedifferentiation. Induction of dedifferentiation resulted in the upregulation of nonmuscle myosin heavy chain expression, a marker of dedifferentiation, and the downregulation of smooth muscle myosin heavy chain expression, a marker of differentiation. Nifedipine significantly inhibited both the induction of these phenotypic changes and upregulation of Akt signaling in these cells. Administration of nifedipine at a low concentration that did not affect blood pressure could inhibit the increase in nonmuscle myosin heavy chain expression and decrease in smooth muscle myosin heavy chain expression in a rat balloon-injury model. Furthermore, nifedipine suppressed neointimal hyperplasia and upregulation of Akt signaling. However, phospho-Akt expression was not suppressed in the regenerating arterial endothelium of the nifedipine-treated rats. The inhibitory effect of the downregulation of Akt signaling by dominant-negative Akt on the induction of VSMC dedifferentiation in the intima was identical to that of nifedipine. In contrast, upregulation of Akt signaling by transfection of the cells with a constitutively active Akt reversed the nifedipine-induced inhibition of VSMC dedifferentiation. In conclusion, nifedipine inhibits VSMC dedifferentiation by suppressing Akt signaling, thereby preventing neointimal thickening. (Hypertension. 2010;56:247-252.)

Orthogonal linear separation analysis: an approach to decompose the complex effects of a perturbagen

“…One of the cellular responses they have is AKT inhibition Lim et al, 2016;Kim & Lee, 2018;Yang et al, 2014). It is consistent that the other compounds around the top of the list, nifedipine (6 th ), resveratrol (7 th and 10 th ), and harmol (8 th ), are potent inhibitors of AKT (Kaimoto et al, 2010;Haider et al, 2005;Abe & Kokuba, 2013). Acacetin, the only flavonoid with a focused structure in the test set, exhibited the highest correlation coefficient, and nifedipine and resveratrol were also ranked at the 4 th and 9 th positions in the list of 122 compounds, respectively (Fig 2E, lower panel).…”

Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway

“…Activation of MAPK family, a down-stream mediator of ROS, is found in diseases associated with vascular remodeling, such as atherosclerosis and hypertension. 31, 32 Akt, which may be regulated by ROS and calcium in SMCs, 33 is another transduction mechanism implicated in the control of cell proliferation and migration. 34 The MAPK family includes three major groups: ERK, p38, and JNK.…”

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

“…This network included the major POAG GWAS hits CAV1 and CAV2 and involved a diverse set of genes involved in a myriad of different physiological functions. CAV1 is needed for the mechanosensitive activation of Akt in vascular smooth muscle cells in response to increased tensile stretch experienced during essential hypertension (Kaimoto et al, 2010) (Xue et al, 2007). In TM cells, elevated OHT also activates Akt, which in turn activates matrix metalloproteinases (MMPs).…”