| 1. |
|
|
| 2. |
- Bandaru, Sashidar, et al.
(författare)
-
Filamin A regulates cardiovascular remodeling
- 2021
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:12
-
Forskningsöversikt (refereegranskat)abstract
- Filamin A (FLNA) is a large actin‐binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C‐ terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells. Localized FLNA mutations associate with cardiovascular malformations in hu-mans. A lack of FLNA in experimental animal models disrupts cell migration during embryogenesis and causes anomalies, including heart and vessels, similar to human malformations. More recently, it was shown that FLNA mediates the progression of myocardial infarction and atherosclerosis. Thus, these latest findings identify FLNA as an important novel mediator of cardiovascular development and remodeling, and thus a potential target for therapy. In this update, we summarized the literature on filamin biology with regard to cardiovascular cell function.
|
|
| 3. |
- Zheng, Xiaowei, et al.
(författare)
-
Hypoxia-induced and calpain-dependent cleavage of filamin-A regulates the hypoxic response. : Hypoxia-induced and calpain-dependent cleavage of filamin-A regulates the hypoxic response.
- 2014
-
Ingår i: Proceedings of the National Academy of Science of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:7, s. 2560-2565
-
Tidskriftsartikel (refereegranskat)abstract
- The cellular response to hypoxia is regulated by hypoxia-inducible factor-1α and -2α (HIF-1α and -2α). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α and promotes tumor growth and angiogenesis. Hypoxia induces a calpain-dependent cleavage of FLNA to generate a naturally occurring C-terminal fragment that accumulates in the cell nucleus. This fragment interacts with the N-terminal portion of HIF-1α spanning amino acid residues 1-390 but not with HIF-2α. In hypoxia this fragment facilitates the nuclear localization of HIF-1α, is recruited to HIF-1α target gene promoters, and enhances HIF-1α function, resulting in up-regulation of HIF-1α target gene expression in a hypoxia-dependent fashion. These results unravel an important mechanism that selectively regulates the nuclear accumulation and function of HIF-1α and potentiates angiogenesis and tumor progression.
|
|
| 4. |
- Zhou, Alex-Xianghua, et al.
(författare)
-
C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions
- 2015
-
Ingår i: Circulation Research. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7330 .- 1524-4571. ; 116:11
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: Myeloid-derived C/EBP-homologous protein (CHOP), an effector of the endoplasmic reticulum stress-induced unfolded protein response, promotes macrophage apoptosis in advanced atherosclerosis, but the role of CHOP in vascular smooth muscle cells (VSMCs) in atherosclerosis is not known. Objective: To investigate the role of CHOP in SM22 alpha(+) VSMCs in atherosclerosis. Methods and Results: Chop(fl/fl) mice were generated and crossed into the Apoe(-/-) and SM22 alpha-CreKI(+) backgrounds. SM22 alpha-CreKI causes deletion of floxed genes in adult SMCs. After 12 weeks of Western-type diet feeding, the content of alpha-actin-positive cells in aortic root lesions was decreased in Chop(fl/fl)SM22 alpha-CreKI(+) Apoe(-/-) versus control Chop(fl/fl)Apoe(-/-) mice, and aortic explant-derived VSMCs from the VSMC-CHOP-deficient mice displayed reduced proliferation. Kruppel-like factor 4 (KLF4), a key suppressor of VSMC proliferation, was increased in lesions and aortic VSMCs from Chop(fl/fl)SM22 alpha-CreKI(+) Apoe(-/-) mice, and silencing Klf4 in CHOP-deficient VSMCs restored proliferation. CHOP deficiency in aortic VSMCs increased KLF4 through 2 mechanisms mediated by the endoplasmic reticulum stress effector activating transcription factor 4: transcriptional induction of Klf4 mRNA and decreased proteasomal degradation of KLF4 protein. Conclusions: These findings in SM22 alpha-CHOP-deficient mice imply that CHOP expression in SM22 alpha(+) VSMCs promotes cell proliferation by downregulating KLF4. The mechanisms involve newly discovered roles of CHOP in the transcriptional and post-translational regulation of KLF4.
|
|
| 5. |
- Zhou, Alex-Xianghua, et al.
(författare)
-
Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy
- 2024
-
Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:8
-
Tidskriftsartikel (refereegranskat)abstract
- Endothelial cell (EC) injury is a crucial contributor to the progression of diabetic kidney disease (DKD), but the specific EC populations and mechanisms involved remain elusive. Kidney ECs (n = 5464) were collected at three timepoints from diabetic BTBRob/ob mice and non-diabetic littermates. Their heterogeneity, transcriptional changes, and alternative splicing during DKD progression were mapped using SmartSeq2 single-cell RNA sequencing (scRNAseq) and elucidated through pathway, network, and gene ontology enrichment analyses. We identified 13 distinct transcriptional EC phenotypes corresponding to different kidney vessel subtypes, confirmed through in situ hybridization and immunofluorescence. EC subtypes along nephrons displayed extensive zonation related to their functions. Differential gene expression analyses in peritubular and glomerular ECs in DKD underlined the regulation of DKD-relevant pathways including EIF2 signaling, oxidative phosphorylation, and IGF1 signaling. Importantly, this revealed the differential alteration of these pathways between the two EC subtypes and changes during disease progression. Furthermore, glomerular and peritubular ECs also displayed aberrant and dynamic alterations in alternative splicing (AS), which is strongly associated with DNA repair. Strikingly, genes displaying differential transcription or alternative splicing participate in divergent biological processes. Our study reveals the spatiotemporal regulation of gene transcription and AS linked to DKD progression, providing insight into pathomechanisms and clues to novel therapeutic targets for DKD treatment.
|
|
