Myocardin Family Members Drive Formation of Caveolae

Abstract

Caveolae are membrane organelles that play roles in glucose and lipid metabolism and in vascular function. Formation of caveolae requires caveolins and cavins. The make-up of caveolae and their density is considered to reflect cell-specific transcriptional control mechanisms for caveolins and cavins, but knowledge regarding regulation of caveolae genes is incomplete. Myocardin (MYOCD) and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation. MRTF-A communicates changes in actin polymerization to nuclear gene transcription. Here we tested if myocardin family proteins control biogenesis of caveolae via activation of caveolin and cavin transcription. Using human coronary artery smooth muscle cells we found that jasplakinolide and latrunculin B (LatB), substances that promote and inhibit actin polymerization, increased and decreased protein levels of caveolins and cavins, respectively. The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB. Overexpression of myocardin and MRTF-A caused 5-10-fold induction of caveolins whereas cavin-1 and cavin-2 were induced 2-3-fold. PACSIN2 also increased, establishing positive regulation of caveolae genes from three families. Full regulation of CAV1 was retained in its proximal promoter. Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs. Viral transduction of myocardin increased the density of caveolae 5-fold in vitro. A decrease of CAV1 was observed concomitant with a decrease of the smooth muscle marker calponin in aortic aneurysms from mice (C57Bl/6) infused with angiotensin II. Human expression data disclosed correlations of MYOCD with CAV1 in a majority of human tissues and in the heart, correlation with MKL2 (MRTF-B) was observed. The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF.

Rosiglitazone drives cavin-2/SDPR expression in adipocytes in a CEBPα-dependent manner

“…Beyond the novel finding that cavin-2/SDPR is controlled by CEBPα/PPARγ in adipocytes, our results also confirm and extend the recent demonstration that myocardin family coactivators control the expression of caveolins and cavins [21]. In our previous study [21] we found that myocardin and MKL1 control gene expression of cavolins and cavins in smooth muscle.…”

“…This study, in conjunction with our previous work [21], thus highlights a considerable divergence between different cells types with regard to transcriptional control mechanisms of caveolar constituents. Such diversity may allow for tissue-specific pharmacological manipulation of caveolar function in diabetes and obesity.…”

“…In our previous study [21] we found that myocardin and MKL1 control gene expression of cavolins and cavins in smooth muscle. Herein, we demonstrate that MKL2, similar to MKL1, has the ability to drive transcription of all caveolins and cavins except cavin-1 (PTRF), in terminally differentiated, primary adipocytes.…”

Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway

“…Expression data for the human coronary artery was downloaded from the GTExPortal.org and TMM normalized as described 34 . Panels A though C show relative expression levels for NOTCH ligands ( A ), receptors ( B ), and coactivators ( C ).…”

Similar regulatory mechanisms of caveolins and cavins by myocardin family coactivators in arterial and bladder smooth muscle

“…Myocardin family coactivators appear unique in that they induce essentially all caveolins and cavins [14]. Several questions remain unanswered with respect to this transcriptional control mechanism, however [4].…”