Biology subjects

Dave, J. M.

Publications and source records attributed to Dave, J. M..

3 recordsLinked to original sources

bioRxiv2024

Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization

Defective elastin and smooth muscle cell (SMC) accumulation characterize both arterial diseases (e.g., atherosclerosis, restenosis and supravalvular aortic stenosis [SVAS]), and physiological ductus arteriosus (DA) closure. Elastin deficiency induces SMC hyperproliferation; however, mechanisms underlying this effect are not well elucidated. Elastin (ELN) is expressed from embryonic day (E) 14 in the mouse aorta. Immunostains of Eln(+/+) and Eln(-/-) aortas indicate that SMCs of the Eln null aorta are first hyperproliferative at E15.5, prior to morphological differences. Bulk RNA-seq reveals that sphingosine kinase 1 (Sphk1) is the most upregulated transcript in Eln(-/-) aortic SMCs at E15.5. Reduced ELN increases levels of transcription factor early growth response 1 (EGR1), resulting in increased SPHK1 levels in cultured human aortic SMCs and in the mouse aorta at E15.5 and P0.5. Aortic tissue from Williams-Beuren Syndrome patients, who have elastin insufficiency and SVAS, also has upregulated SPHK1 expression. SMC-specific Sphk1 deletion or pharmacological inhibition of SPHK1 attenuates SMC proliferation and mitigates aortic disease, leading to extended survival of Eln(-/-) mice. In addition, EGR1 and SPHK1 are increased in the wild-type mouse DA compared to adjacent descending aorta. Treatment with a SPHK1 inhibitor attenuates SMC proliferation and reduces SMC accumulation, leading to DA patency. In sum, SPHK1 is a key node in elastin deficiency-induced hypermuscularization, and inhibiting this kinase may be a therapeutic strategy for SVAS and select congenital heart diseases in which a patent DA maintains circulation. One Sentence SummarySphingosine kinase 1-induced by defective elastin promotes muscularization in pathological aortic stenosis and physiological ductus arteriosus occlusion.

developmental biology↗

bioRxiv2024

Epigenetic Remodeling in Human Coronary Artery Smooth Muscle Cell Phenotypic Switching

BackgroundSmooth muscle cell (SMC) dedifferentiation contributes to repair and remodeling, but also cardiovascular pathologies. To understand this plasticity, the epigenetic landscape in SMC phenotypic switching was profiled. MethodsGenome-wide analyses of histone modifications (ChIP-seq), chromatin architecture (ATAC-seq), and transcriptomes (RNA-seq) were performed on human coronary artery SMCs (CASMC) treated with rapamycin (contractile phenotype) and PDGF-BB (synthetic phenotype). ResultsAnalyses of differentially acetylated promoter regions identified ZEB and ZBT7A as novel enriched regulatory motifs. There were more changes in the enhancer epigenome than in promoters in CASMC phenotypic switching. Rapamycin-activated enhancers were associated with differentiation and TGF-{beta} signaling pathways and were most enriched in TEAD, SRF and SMAD motifs, whereas PDGF-induced enhancers were associated with ERK signaling and migration pathways, and were most enriched in ETV4, SOX5, and FOS motifs. GATA, TEAD, and SMCA1 motifs were enriched in CASMC enhancer open chromatin compared to other cell types. Candidate enhancers with single nucleotide polymorphisms linked to cardiovascular disease were markedly enriched in active enhancers and super enhancers and showed significant activity in reporter assays. In CASMC promoters and enhancers, common regulatory motifs were often enriched in both the differentiated and dedifferentiated phenotypes, suggesting that differential cofactor binding, as occurs with SRF at CArG elements, may be a more widespread mechanism underlying phenotypic switching. ConclusionsThese data identify novel regulatory elements engaged in SMC phenotypic switching and provide a comprehensive profile of SMC promoters, enhancers, super enhancers, and chromatin accessibility as a significant resource for studies of CASMC phenotype. Research PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIThis work identifies key regulatory elements and widespread changes in chromatin accessibility engaged in SMC phenotypic switching, including novel motifs enriched in promoters and enhancers. In CASMC promoters and enhancers, common regulatory motifs were often enriched in both the differentiated and dedifferentiated phenotypes, suggesting that differential cofactor binding, as occurs with SRF at CArG elements, may be a more widespread mechanism underlying phenotypic switching. C_LIO_LIThis work identifies distinct enhancer profiles: enhancers activated by rapamycin were associated with TGF-{beta} signaling and differentiation, while PDGF-induced enhancers were associated with ERK signaling and migration. C_LIO_LIEnhancer elements containing single nucleotide polymorphisms (SNPs) associated with cardiovascular disease from genome wide association studies (GWAS) showed notable enrichment across active enhancers and super enhancers. Select enhancers demonstrated statistically significant activity in reporter gene assays. C_LI What Question Should Be Addressed Next?O_LIThe cis regulatory elements identified in this work suggest new transcription factors that can be tested to determine whether and how they may influence SMC phenotypic modulation. C_LIO_LIThese studies could be extended to other stimuli to identify epigenomic signatures associated with CASMC transitions to other phenotypes including macrophages and chondrocytes. C_LI

genomics↗

bioRxiv2023

Loss of presenilin-1 in smooth muscle cells ameliorates elastin aortopathy

Smooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, such as atherosclerosis, pulmonary hypertension and supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin insufficiency activates the Notch pathway in aortic SMCs, resulting in hypermuscularization. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of specific catalytic subunits PSEN-1 or PSEN-2 in elastin aortopathy is not defined. This study utilizes genetic approaches to query the role of PSEN-1/2 in the pathogenesis of elastin mutant mice, which model human SVAS. Although endothelial cell-specific Psen1 deletion does not improve elastin aortopathy, deletion of either Psen1 in SMCs or Psen2 globally attenuates Notch downstream gene expression and SMC proliferation, mitigating aortic disease. With SMC-specific Psen1 deletion in elastin nulls, these rescue effects are more robust and in fact, survival is increased. On the background of Psen1 deletion in SMCs, global Psen2 deletion yields additional benefits in regard to elastin aortopathy. Finally, SMC deletion of Psen1 also attenuates hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics SVAS. Taken together, these findings put forth SMC PSEN-1 as a potential therapeutic target in elastin aortopathy.

developmental biology↗