Increased TGFβ1 and SMAD3 Contribute to Age-Related Aortic Valve Calcification

Chakrabarti, Mrinmay; Bhattacharya, Aniket; Gebere, Mengistu G; Johnson, John Asher; Ayub, Zeeshan A.; Chatzistamou, Ioulia; Vyavahare, Narendra R.; Azhar, Mohamad

doi:10.3389/fcvm.2022.770065

Cited by 7 publications

(3 citation statements)

References 79 publications

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“…Accordingly, semi-dominant COL4A1 and COL4A2 mutations cause Gould syndrome characterized primary by cerebrovascular manifestation in which TGF-β signaling is overactivated [ 24 ]. Increased TGF-β1 and TGF-β-dependent SMAD3 signaling are associated with age-related aortic valve calcification in klotho knockout mice [ 25 ]. Interestingly, DAF-7/TGF-β regulates longevity through DAF-2/insulin signaling in C .…”

Section: Discussionmentioning

confidence: 99%

Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans

Shibata,

Huang,

Yoshida

et al. 2024

PLoS ONE

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The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloprotease MIG-17 plays a crucial role in the migration of gonadal distal tip cells (DTCs) in Caenorhabditis elegans. MIG-17 is secreted from the body wall muscle cells and localizes to the basement membranes (BMs) of various tissues including the gonadal BM where it regulates DTC migration through its catalytic activity. Missense mutations in the BM protein genes, let-2/collagen IV a2 and fbl-1/fibulin-1, have been identified as suppressors of the gonadal defects observed in mig-17 mutants. Genetic analyses indicate that LET-2 and FBL-1 act downstream of MIG-17 to regulate DTC migration. In addition to the control of DTC migration, MIG-17 also plays a role in healthspan, but not in lifespan. Here, we examined whether let-2 and fbl-1 alleles can suppress the age-related phenotypes of mig-17 mutants. let-2(k196) fully and fbl-1(k201) partly, but not let-2(k193) and fbl-1(k206), suppressed the senescence defects of mig-17. Interestingly, fbl-1(k206), but not fbl-1(k201) or let-2 alleles, exhibited an extended lifespan compared to the wild type when combined with mig-17. These results reveal allele specific interactions between let-2 or fbl-1 and mig-17 in age-related phenotypes, indicating that basement membrane physiology plays an important role in organismal aging.

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Section: Discussionmentioning

confidence: 99%

Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans

Shibata,

Huang,

Yoshida

et al. 2024

PLoS ONE

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“…Related to this observation, a previous study reported that FGF23 induces the phosphorylation of SMAD2/3, a critical mediator of TGF-β signaling 36 . As the SMAD signaling pathway contributes to the development of CAVD 37 , 38 . Studies are needed to evaluate the relative role of the TGF-β/SMAD signaling pathway in the mechanism underlying FGF23-induced valvular cell fibrogenesis and calcification.…”

Section: Discussionmentioning

confidence: 99%

Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease

The,

Zhai,

Yao

et al. 2024

Int. J. Biol. Sci.

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Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear. We hypothesized that FGF23 mediates CKD-induced CAVD by enhancing aortic valve interstitial cell (AVIC) fibrosis and calcification, while soluble Klotho inhibits FGF23 effect. Methods and Results: In an old mouse model of CKD, kidney damages were accompanied by aortic valve thickening and calcification. FGF23 levels in plasma and aortic valve were increased, while Klotho levels were decreased. Recombinant FGF23 elevated the inflammatory, fibrogenic, and osteogenic activities in AVICs. Neutralizing antibody or shRNA targeting FGF23 suppressed the pathobiological activities in AVICs from valves affected by CAVD. FGF23 exerts its effects on AVICs via FGF receptor (FGFR)/Yes-associated protein (YAP) signaling, and inhibition of FGFR/YAP reduced FGF23's potency in AVICs. Recombinant Klotho downregulated the pathobiological activities in AVICs exposed to FGF23. Incubation of FGF23 with Klotho formed complexes and decreased FGF23's potency. Further, treatment of CKD mice with recombinant Klotho attenuated aortic valve lesions. Conclusion: This study demonstrates that CKD induces FGF23 accumulation, Klotho insufficiency and aortic valve lesions in old mice. FGF23 upregulates the inflammatory, fibrogenic and osteogenic activities in AVICs via the FGFR/YAP signaling pathway. Soluble Klotho suppresses FGF23 effect through molecular interaction and is capable of mitigating CKD-induced CAVD.

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“…This gene could improve chronic kidney disease and some cardiovascular diseases. Studies have shown that the formation of calcified nodules in the aortic valves of klotho-deficient mice is associated with increased expression of TGF-β1 and elevated levels of the activated forms of Smad2, Smad3, Smad1/5, p38, and ERK1/2 MAPK [ 139 ]. Klotho protein can be used to treat aging-related vascular fibrosis.…”

Section: Targeting Tgf-β In Aging-related Fibrosismentioning

confidence: 99%

TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis

Ren¹,

Miao²,

Wang³

et al. 2023

Aging and disease

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Fibrosis is the abnormal accumulation of extracellular matrix proteins such as collagen and fibronectin. Aging, injury, infections, and inflammation can cause different types of tissue fibrosis. Numerous clinical investigations have shown a correlation between the degree of liver and pulmonary fibrosis in patients and telomere length and mitochondrial DNA content, both of which are signs of aging. Aging involves the gradual loss of tissue function over time, which results in the loss of homeostasis and, ultimately, an organism's fitness. A major feature of aging is the accumulation of senescent cells. Senescent cells abnormally and continuously accumulate in the late stages of life, contributing to age-related fibrosis and tissue deterioration, among other aging characteristics. Furthermore, aging generates chronic inflammation, which results in fibrosis and decreases organ function. This finding suggests that fibrosis and aging are closely related. The transforming growth factorbeta (TGF-β) superfamily plays a crucial role in the physiological and pathological processes of aging, immune regulation, atherosclerosis, and tissue fibrosis. In this review, the functions of TGF-β in normal organs, aging, and fibrotic tissues is discussed: TGF-β signalling is altered with age and is an indicator of pathology associated with tissue fibrosis. In addition, this review discusses the potential targeting of noncoding.

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Increased TGFβ1 and SMAD3 Contribute to Age-Related Aortic Valve Calcification

Cited by 7 publications

References 79 publications

Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans

Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans

Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease

TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis

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