Junb regulates arterial contraction capacity, cellular contractility, and motility via its target Myl9 in mice

Abstract

Cellular contractility and, thus, the ability to alter cell shape are prerequisites for a number of important biological processes such as cytokinesis, movement, differentiation, and substrate adherence. The contractile capacity of vascular smooth muscle cells (VSMCs) is pivotal for the regulation of vascular tone and thus blood pressure and flow. Here, we report that conditional ablation of the transcriptional regulator Junb results in impaired arterial contractility in vivo and in vitro. This was exemplified by resistance of Junb-deficient mice to DOCA-salt-induced volume-dependent hypertension as well as by a decreased contractile capacity of isolated arteries. Detailed analyses of Junb-deficient VSMCs, mouse embryonic fibroblasts, and endothelial cells revealed a general failure in stress fiber formation and impaired cellular motility. Concomitantly, we identified myosin regulatory light chain 9 (Myl9), which is critically involved in actomyosin contractility and stress fiber assembly, as a Junb target. Consistent with these findings, reexpression of either Junb or Myl9 in Junb-deficient cells restored stress fiber formation, cellular motility, and contractile capacity. Our data establish a molecular link between the activator protein-1 transcription factor subunit Junb and actomyosin-based cellular motility as well as cellular and vascular contractility by governing Myl9 transcription.

miR-663 and the miRaculous Vascular Smooth Muscle Phenotypic Switch

“…According to their findings summarized in the Figure, miR-663 overexpression inhibits platelet-derived growth factor-BB-induced JUNB and MYL9 expression and subsequent VSMC migration, as well as neointima formation. 23 In line with these observations, previous work by Licht et al 17 shows that the JUNB-MYL9 axis is required for cell migration. Moreover, Li et al 23 provide evidence that miR-663 overexpression inhibits neointima formation and is associated with a decrease in JUNB abundance and VSMC proliferation.…”

“…On the other hand, diminishing the expression of JUNB and thus MYL9 would eventually render the SMCs unable to exert contractile responses and limit their regular function in maintaining blood pressure. This can be deduced from the study of Licht et al 17 showing that ablation of Junb results in a severely diminished norepinephrine-induced constriction and impaired pressure-induced contractile responses. From a physiological point of view, therapies based on forced miR-663 expression for the treatment of arterial diseases may, therefore, act as a double-edged sword as they would limit SMC proliferation and, therefore, neointima formation but concomitantly compromise the contractile capacity of VSMCs.…”

“…Moreover, Li et al 23 provide evidence that miR-663 overexpression inhibits neointima formation and is associated with a decrease in JUNB abundance and VSMC proliferation. However, loss of JUNB did not affect proliferation of medial SMCs during hypertension-induced remodeling of the arterial wall, 17 suggesting that JUNB may not control all aspects of the phenotypic switch. Amazingly, the experimental setting used by Li et al 23 worked because the miR-663-binding site within the JUNB 3′-untranslated region is highly conserved from human to rodents although miR-663 is only expressed in primates.…”

“…13,14 The activator protein-1 subunit JUNB is critically involved in angiogenic processes, 15,16 as well as in the control of vascular homeostasis, by governing the migration and contraction capacity of VSMCs through transcriptional activation of the myosin light chain-2/MYL9-a crucial element of the contractile apparatus. 17 Recently, an additional mode of control was delineated, namely the negative regulation of gene expression by microRNAs (miRNA) that are small noncoding RNAs. miRNAs are generated from primary RNA precursors that are subjected to 2 cleavage steps executed by the endoribunucleases Drosha and Dicer.…”

Screening of key genes of unruptured intracranial aneurysms by using DNA microarray data analysis techniques

“…Furthermore, hyper-methylated FAM5C and MYLK genes can be used as potential biomarkers for the diagnosis of gastric cancer (Chen et al, 2012), MYLK polymorphisms have been suggested to influence increases in blood eosinophil levels among asthmatic patients (Lee et al, 2009), and MYLK is also a novel coronary artery disease susceptibility gene (Wang et al, 2007). Myosin light chain 9 (MYL9; also known as MLC20, RLC-C, or Mylc2c) is one regulator of the myosin light chain polypeptide (Licht et al, 2010). Previous studies have shown that MYL9 is critical in vascular function and remodeling processes with age (Shehadeh et al, 2011), and MYL9 is a major platelet protein based on abundance (Marcus et al, 2000;O'Neill et al, 2002;McRedmond et al, 2004;Sun et al, 2007).…”