title: 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.
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Katarzyna K
authors.initials: KK
authors.lastname: Krawczyk
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Yao Mattisson
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Mari
authors.initials: M
authors.lastname: Ekman
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Oskolkov
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Rebecka
authors.initials: R
authors.lastname: Grantinge
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kotowska
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Olde
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Albinsson
authors.affiliation: Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Miano
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Catarina
authors.initials: C
authors.lastname: Rippe
authors.affiliation: Department of Experimental Medical Science, BMC D12, Lund University, Lund, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Swärd
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1 / Q000032:analysis / Q000235:genetics; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000099251:Myocardin
chemical_list: D000199:Actins; D051242:Caveolin 1; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D000099251:Myocardin; C112745:Cavin1 protein, mouse