P311 induces a TGF-β1–independent, nonfibrogenic myofibroblast phenotype

Pan, Desi; Zhe, Xiaoning; Jakkaraju, Sandhya; Taylor, Gregory A.; Schuger, Lucia

doi:10.1172/jci200215614

Cited by 14 publications

(22 citation statements)

References 42 publications

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“…22 GGF2 also decreased expression of the gene encoding P311 protein, which induces TGFb activation and conversion of fibroblasts to myoFbs. 23 Further analysis of microarray results revealed a potential role for GGF2 in activation of AHR (aka dioxin receptor), an inducible transcription factor important for xenobiotic detox- EGF indicates epidermal growth factor; NRG-1b, neuregulin-1b. *NPR3 was down-regulated in low dose NRG-1b-treated swine but up-regulated (2.2-fold) in swine that received the higher dose.…”

Section: Discussionmentioning

confidence: 99%

Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

Galindo

Kasasbeh

Murphy

et al. 2014

JAHA

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BackgroundNeuregulin‐1β (NRG‐1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG‐1β improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post‐MI swine, as well as potential mechanisms for anti‐remodeling effects.Methods and ResultsMI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post‐MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post‐MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end‐diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2‐treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2‐treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG‐1β reduces myoFbs, and suppresses TGFβ‐induced phospho‐SMAD3 as well as αSMA expression.ConclusionsThese results suggest that GGF2/NRG‐1β prevents adverse remodeling after injury in part via anti‐fibrotic effects in the heart.

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Section: Discussionmentioning

confidence: 99%

Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

Galindo

Kasasbeh

Murphy

et al. 2014

JAHA

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“…JUNB is a growth-promoting transcription factor that is downregulated in all systemic atrophy states (5). The most suppressed mRNA, P311, is also involved in smooth muscle differentiation (60) and has been reported by others to be down-regulated in skeletal muscle after denervation (61) (Fig. 5E).…”

Section: Atrogenes Common To Both Disuse and Systemic Atrophymentioning

confidence: 67%

Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases

et al. 2006

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We previously identified a common set of genes, termed atrogenes, whose expression is coordinately induced or suppressed in muscle during systemic wasting states (fasting, cancer cachexia, renal failure, diabetes). To determine whether this transcriptional program also functions during atrophy resulting from loss of contractile activity and whether atrogene expression correlates with the rate of muscle weight loss, we used cDNA microarrays and RT-polymerase chain reaction to analyze changes in mRNA from rat gastrocnemius during disuse atrophy induced by denervation or spinal cord isolation. Three days after Den or SI, the rate of muscle weight loss was greatest, and 78% of the atrogenes identified during systemic catabolic states were induced or repressed. Of particular interest were the large inductions of key ubiquitin ligases, atrogin-1 (35- to 44-fold) and MuRF1 (12- to 22-fold), and the suppression of PGC-1alpha and PGC-1beta coactivators (15-fold). When atrophy slowed (day 14), the expression of 92% of these atrogenes returned toward basal levels. At 28 days, the atrophy-inducing transcription factor, FoxO1, was still induced and may be important in maintaining the "atrophied" state. Thus, 1) the atrophy associated with systemic catabolic states and following disuse involves similar transcriptional adaptations; and 2) disuse atrophy proceeds through multiple phases corresponding to rapidly atrophying and atrophied muscles that involve distinct transcriptional patterns.

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“…P311 is an 8 kDa protein first found in neurons late in brain development and in invasive glioblastoma (67). P311 appears to be involved in smooth muscle differentiation in myofibroblasts by driving expression of actin and other muscle-specific genes (68).…”

Section: Genes Involved In Muscle Growth and Differentiationmentioning

confidence: 99%

Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression

et al. 2004

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Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin-induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair-fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin-1/MAFbx and MuRF-1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down-regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up-regulated (lipin, metallothionein, AMP deaminase, RNA helicase-related protein, TG interacting factor) and several growth-related mRNAs were down-regulated (P311, JUN, IGF-1-BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.

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P311 induces a TGF-β1–independent, nonfibrogenic myofibroblast phenotype

Cited by 14 publications

References 42 publications

Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases

Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression

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