Small proline‐rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts

Saraswati, Sarika; Lietman, Caressa; Li, Bin; Mathew, Sijo; Zent, Roy; Young, Pampee P.

doi:10.1096/fj.201902815r

Cited by 23 publications

(14 citation statements)

References 70 publications

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“…Multiple studies have shown the crucial roles of integrin and integrin-binding proteins such as Talin, Vinculin, Melusin, focal adhesion kinase (FAK) and integrin-linked kinase (ILK) in the pathogenesis of cardiac diseases through regulation of MAPKs [33,35,[37][38][39][40]. Consistent with our in vivo and in vitro findings, mice with deficiency of melusin, another muscle-specific integrin-binding protein, displayed a similar detrimental cardiac phenotype when challenged with PO.…”

Section: Discussionsupporting

confidence: 87%

Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload

Shahzadi

Qaisar

Ahmad

2021

Preprint

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Nicotinamide riboside kinase-2 (NRK-2) has recently emerged as a critical regulator of cardiac remodeling however, underlying molecular mechanisms is largely unknown. To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric parameters as well as increased fetal genes ANP and BNP expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II- induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a critical regulator of JNK MAP kinase where NRK-2 overexpression in human cardiomyocytes markedly suppressed the angiotensin II- induced JNK activation. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload- induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy, interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation.

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Section: Discussionsupporting

confidence: 87%

Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload

Shahzadi

Qaisar

Ahmad

2021

Preprint

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“…A PCR array ( Supplemental Figure 13 ) demonstrated that Smad7 loss in fibroblasts is associated with markedly accentuated synthesis of mRNAs encoding structural matrix proteins (including Col1a1 , Col3a1 [collagen type III α1], Col5a1 [collagen type V α1], Col6a1 [collagen type VI α1], and Fn [fibronectin]; Figure 5, A–H ), basement membrane genes (including those encoding laminins and collagen IV chains; Supplemental Figure 14, A–G ), and matricellular proteins (including Postn , Tsp1 [thrombospondin 1], Tsp2 , Ccn2 [cellular communication network factor 2], and Vcan [versican]; Figure 5, A–H , and Supplemental Figure 14 ). Smad7 loss also accentuated fibroblast expression of Itgb1 ( Supplemental Figure 14I ), which encodes a TGF-β–inducible surface protein (integrin β1) with an important role in fibroblast activation ( 22 ) and proliferation ( 23 ). Moreover, Smad7 loss had profound effects on expression of genes associated with matrix remodeling, reducing Mmp1a levels and increasing expression of Mmp2 , Timp1 , Timp2 , and Adamts family members ( Supplemental Figure 15 ).…”

Section: Resultsmentioning

confidence: 99%

Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure

Humeres¹,

Shinde²,

Hanna³

et al. 2022

Journal of Clinical Investigation

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Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts. However, TGF-β–driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7, may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of nonreperfused infarction, Smad3 activation triggered Smad7 synthesis in α-SMA + infarct myofibroblasts, but not in α-SMA – PDGFRα + fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure–related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 effects on TGF-β cascades involved deactivation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with ErbB2 in a TGF-β–independent manner and restrained ErbB1/ErbB2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins, and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β–induced negative feedback mechanism that inhibits postinfarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-β–independent fibrogenic actions of ErbB2.

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“…ECM remodelling and altered cell–substrate interactions are crucial not only for cell anchorage, but also in regulating several cell functions [ 46 , 47 , 48 , 49 ]. To determine if collagen I impacts on cell behaviour, immunoblotting determined whole cell expression of proteins central to tubulointerstitial fibrosis in lysates from cells cultured on collagen I alone or following co-incubation with TGFβ1 (10 ng/mL) for 48 h. As expected, the pro-fibrotic cytokine increased expression of fibronectin to 314.8 ± 41.4% as compared to control, whilst minimal changes were observed in cells cultured on collagen I alone ( Figure 2 C).…”

Section: Resultsmentioning

confidence: 99%

Collagen I Modifies Connexin-43 Hemichannel Activity via Integrin α2β1 Binding in TGFβ1-Evoked Renal Tubular Epithelial Cells

Potter

Price

Cliff

et al. 2021

IJMS

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Chronic Kidney Disease (CKD) is associated with sustained inflammation and progressive fibrosis, changes that have been linked to altered connexin hemichannel-mediated release of adenosine triphosphate (ATP). Kidney fibrosis develops in response to increased deposition of extracellular matrix (ECM), and up-regulation of collagen I is an early marker of renal disease. With ECM remodeling known to promote a loss of epithelial stability, in the current study we used a clonal human kidney (HK2) model of proximal tubular epithelial cells to determine if collagen I modulates changes in cell function, via connexin-43 (Cx43) hemichannel ATP release. HK2 cells were cultured on collagen I and treated with the beta 1 isoform of the pro-fibrotic cytokine transforming growth factor (TGFβ1) ± the Cx43 mimetic Peptide 5 and/or an anti-integrin α2β1 neutralizing antibody. Phase microscopy and immunocytochemistry observed changes in cell morphology and cytoskeletal reorganization, whilst immunoblotting and ELISA identified changes in protein expression and secretion. Carboxyfluorescein dye uptake and biosensing measured hemichannel activity and ATP release. A Cytoselect extracellular matrix adhesion assay assessed changes in cell-substrate interactions. Collagen I and TGFβ1 synergistically evoked increased hemichannel activity and ATP release. This was paralleled by changes to markers of tubular injury, partly mediated by integrin α2β1/integrin-like kinase signaling. The co-incubation of the hemichannel blocker Peptide 5, reduced collagen I/TGFβ1 induced alterations and inhibited a positive feedforward loop between Cx43/ATP release/collagen I. This study highlights a role for collagen I in regulating connexin-mediated hemichannel activity through integrin α2β1 signaling, ahead of establishing Peptide 5 as a potential intervention.

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Small proline‐rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts

Cited by 23 publications

References 70 publications

Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload

Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload

Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure

Collagen I Modifies Connexin-43 Hemichannel Activity via Integrin α2β1 Binding in TGFβ1-Evoked Renal Tubular Epithelial Cells

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