Expression of fibulin-6 in failing hearts and its role for cardiac fibroblast migration

Chowdhury, Arpita; Herzog, Christine; Hasselbach, Lisa; Khouzani, Houra Loghmani; Zhang, Jinli; Hammerschmidt, Matthias; Rudat, Carsten; Kispert, Andreas; Gaestel, Matthias; Menon, Manoj B.; Tudorache, I.; Hilfiker‐Kleiner, Denise; Mühlfeld, Christian; Schmitto, Jan D.; Müller, Martin; Theilmeier, Gregor

doi:10.1093/cvr/cvu161

Cited by 28 publications

(35 citation statements)

References 47 publications

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“…A similar interplay between HMCN1 and TGF-␤ was recently shown in cardiac fibroblasts, where HMCN1 was induced in infarcted myocardium during the early and the late phase of infarct healing (6). This is consistent with the fact that, in mice, HMCN1 is generally expressed in tissues experiencing high mechanical stress (46).…”

Section: Discussionsupporting

confidence: 83%

“…We then focused on Hmcn1, whose modulation was particularly highlighted in the annotation cluster 2 as part of the genes of the ECM and BM ( Table 2). Because of the large molecular weight of HMCN1 protein (600 kDa), which prevented its quantitative evaluation by Western blot (6,46), we studied the spatial and cellular distribution of HMCN1 by immunofluorescence staining. Double-labeling immunofluorescence revealed that HMCN1 was expressed predominantly in the glomerulus and colocalized with synaptopodin (syn), which is a podocyte-specific marker, and, to a lesser extent, with laminin ␤ 2 , which is a glomerular basement membrane marker (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Hemicentin 1 influences podocyte dynamic changes in glomerular diseases

Toffoli

Zennaro

Winkler

et al. 2018

American Journal of Physiology-Renal Physiology

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Different complex mechanisms control the morphology of podocyte foot processes and their interactions with the underlying basement membrane. Injuries to this system often cause glomerular dysfunction and albuminuria. The present study aimed at identifying early markers of glomerular damage in diabetic nephropathy. For this purpose, we performed a microarray analysis on kidneys of 3-wk-old peroxisome proliferator-activated receptor-γ (PPARγ)-null and AZIP/F1 mice, which are two models of diabetic nephropathy due to lipodystrophy. This was followed by functional annotation of the enriched clusters of genes. One of the significant changes in the early stages of glomerular damage was the increase of hemicentin 1 (HMCN1). Its expression and distribution were then studied by real-time PCR and immunofluorescence in various models of glomerular damage and on podocyte cell cultures. HMCN1 progressively increased in the glomeruli of diabetic mice, according to disease severity, as well as in puromycin aminonucleoside (PA)-treated rats. Studies on murine and human podocytes showed an increased HMCN1 deposition upon different pathological stimuli, such as hyperglycemia, transforming growth factor-β (TGF-β), and PA. In vitro silencing studies showed that HMCN1 mediated the rearrangements of podocyte cytoskeleton induced by TGF-β. Finally, we demonstrated an increased expression of HMCN1 in the kidneys of patients with proteinuric nephropathies. In summary, our studies identified HMCN1 as a new molecule involved in the dynamic changes of podocyte foot processes. Its increased expression associated with podocyte dysfunction points to HMCN1 as a possible marker for the early glomerular damage occurring in different proteinuric nephropathies.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Hemicentin 1 influences podocyte dynamic changes in glomerular diseases

Toffoli

Zennaro

Winkler

et al. 2018

American Journal of Physiology-Renal Physiology

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“…That HMCN1 proteins assemble into tracks suggests a role for HMCN1 in structural support. Data from a mouse model of myocardial infarction and from cultured cardiac fibroblasts suggest that HMCN1 functions in myocardial remodeling by regulating profibrotic TGB‐β responses . It is possible that HMCN1 also plays important roles in remodeling of the tissues examined in our study during development and in response to injury.…”

Section: Discussionmentioning

confidence: 81%

Mammalian hemicentin 1 is assembled into tracks in the extracellular matrix of multiple tissues

Lin

Pope

Sasaki

et al. 2020

Developmental Dynamics

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Background: Hemicentins (HMCNs) are a family of extracellular matrix proteins first identified in Caenorhabditis elegans, with two orthologs (HMCN1 and 2) in vertebrates. In worms, HMCN is deposited at specific sites where it forms long, fine tracks that link two tissues by connecting adjacent basement membranes (BMs). By generating CRISPR/Cas9-mediated Hmcn1 and Hmcn2 knockout mice, we tested the hypothesis that HMCNs perform similar functions in mammals.Results: Hmcn1 −/− mice were viable and fertile. Using new, knockout mousevalidated HMCN1 antibodies, HMCN1 was detected in wild-type mice as fine tracks along the BM of hair and whisker follicles, in the sclera of the eyes, and in the lumen of some lymphoid conduits. It was also observed in the mesangial matrix of the kidney glomerulus. However, HMCN1 deficiency did not affect the functions of these tissues, including adherence of coat hairs and whiskers, the sieving function of lymphoid conduits, or the immune response to injected antigens. HMCN2 deficiency did not lead to any discernible phenotypes on its own or when combined with HMCN1 deficiency.Conclusion: That Hmcn1 −/− , Hmcn2 −/− , and Hmcn1/2 double knockout mice did not display any overt phenotypes implicates compensation by other members of the fibulin family. K E Y W O R D Sbasement membrane, hair follicle, lymphoid conduits, matrix protein, sclera, whisker follicle

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“…In the present study, a mutation in HMCN1 (c.T9776C), which encodes for an extracellular protein belonging to the immunoglobulin superfamily, was annotated as deleterious by PolyPhe2, LRT and the MutationTaster databases (32). Furthermore, HMCN1 has previously been revealed to be predominantly expressed in the vascular endothelial cells of coronary arteries and sparsely expressed in the endocardial endothelium in the mouse heart, which may have an important role in myocardial remodeling following myocardial infarction by affecting cardiac fibroblast migration via TGF-β1 signaling (33). Furthermore, a previous study using animal models and induced pluripotent stem cell-derived cardiomyocytes demonstrated that abnormal regulation of TGF-β may represent a potential mechanism underlying LVNC (34).…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing identifies novel candidate mutations in a Chinese family with left ventricular noncompaction

et al. 2018

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Left ventricular noncompaction (LVNC) is an inherited cardiomyopathy involving numerous genes. To identify novel candidate causal mutations, a whole exome sequencing study was performed on a Chinese LVNC family. Exons of the most prevalent pathogenic genes of LVNC (myosin heavy chain 7 and actin, α‑cardiac muscle 1) were sequenced, although no mutations were identified. Following this, Burrows‑Wheeler Aligner, PICARD and Genome Analysis Toolkit (v.2.8) were used to analyze the exome sequencing data. Non‑silent single nucleotide variants (SNVs) that were identified in patients with LVNC, although not in the healthy individual, were investigated further using SNV prioritization via the integration of genomic data (SPRING) based on P‑values. Co‑expressed gene enrichment analysis was performed using Genotype Tissue Expression (GTEx) data in order to investigate the potential roles of the genes containing SNVs in the myocardium. In the Chinese LVNC family, seven novel SNVs were identified that were only present in patients with LVNC and annotated by SPRING with P<0.05. Among these SNVs, hemicentin 1 [c. thymine (T) 9776 cytosine (C)], tolloid like 2 [c. cytosine (C) 2615 thymine (T)], fms related tyrosine kinase 3 [c. guanine (G) 976 adenine (A)] and nucleotide binding protein like [c. guanine (G) 91 thymine (T)] were located in conserved regions and annotated as deleterious by PolyPhen2, LRT and MutationTaster database analyses. Based on GTEx data, it was revealed that NUBPL was co‑expressed with almost all previously established LVNC pathogenic genes. Furthermore, the results of the present study demonstrated that genes co‑expressed with NUBPL were additionally enriched in the Notch signaling pathway. In addition, the results revealed numerous novel mutations that may be causal SNVs for the development of LVNC in the family involved in the present study.

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Expression of fibulin-6 in failing hearts and its role for cardiac fibroblast migration

Abstract: Fibulin-6, a fibroblast-released ECM protein, may play an important role during MR by imparting an effect on CF migration in close and complementary interplay with TGF-β1 signalling.

Cited by 28 publications

References 47 publications

Hemicentin 1 influences podocyte dynamic changes in glomerular diseases

Hemicentin 1 influences podocyte dynamic changes in glomerular diseases

Mammalian hemicentin 1 is assembled into tracks in the extracellular matrix of multiple tissues

Whole exome sequencing identifies novel candidate mutations in a Chinese family with left ventricular noncompaction

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