Increased Expression of Growth Differentiation Factor-15 in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Meadows, Christina A.; Risbano, Michael G.; Zhang, Li; Geraci, Mark W.; Tuder, Rubin M.; Collier, David H.; Bull, Todd

doi:10.1378/chest.10-0302

Cited by 65 publications

(59 citation statements)

References 26 publications

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“…It is secreted as a pro-peptide and cleaved to form a dimeric mature protein of 224 amino acids [14]. GDF-15 expression increased in response to stress, hypoxia and inflammation in vitro [14,17] and in a variety of animal and human chronic disease settings [13,17,18]. All the patients in this study underwent the significant acute inflammatory insult of cardiac surgery and as expected circulating GDF-15 rose acutely in all patients.…”

Section: Discussionsupporting

confidence: 64%

“…These factors are all thought to be important in the development of ICUAP [7]. GDF-15 is increasingly implicated in several disease processes including cardiovascular disease [14], multiple cancers [15][16][17], pulmonary artery hypertension [18] and importantly cachexia [19]. Furthermore in a mouse model of cardiac hypertrophy GDF-15 transgenic mice were resistant to cardiac hypertrophy and exposure to circulating GDF-15 limited cardiac myocyte hypertrophy [20].…”

Section: Introductionmentioning

confidence: 99%

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Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Bloch

Lee

Wort

et al. 2013

Critical Care Medicine

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Objectives: Acute muscle wasting in the critically ill is common, and causes significant morbidity. In a novel human model of acute muscle wasting following cardiac surgery, known or potential circulating modulators of muscle mass: insulin-like growth factor-1 (IGF-1), myostatin and growth and differentiation factor-15 (GDF-15), were measured over a week. It was hypothesised that patients who developed acute muscle wasting would show distinct patterns of change in these mediators.Design: A prospective longitudinal observational study of high-risk elective cardiac surgical patients identifying, by ultrasound, those developing muscle wasting.Setting: Tertiary cardiothoracic referral centre: Royal Brompton Hospital, London, UK.Patients: 42 patients undergoing elective high-risk cardiothoracic surgery.Interventions: Circulating IGF-1, myostatin and GDF-15 were assayed pre-operatively and over the first week post-operatively. The ability of GDF-15 to cause muscle wasting in vitro was determined in C2C12 myotubes. Measurements and main results: 23 of 42 patients (55%) developed quadriceps atrophy. There wasan acute decrease in IGF-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma GDF-15 concentrations increased in all patients. This increase in GDF-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p<0.01), but recovered in the non-wasting group (p>0.05). IGF-1 did not recover in those who developed muscle wasting (day 7 compared with baseline, p<0.01) but did in the nonwasting group (p>0.05). Finally, we demonstrated that GDF-15 caused atrophy of myotubes in vitro. Conclusion:These data support the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. GDF-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with Intensive care unit acquired paresis and other forms of acute muscle wasting.Abstract word count: 292

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Bloch

Lee

Wort

et al. 2013

Critical Care Medicine

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“…Our data reveal that elevated circulating GDF-15 levels are highly indicative of worsened lung function. Previously, Meadows et al reported elevated GDF-15 levels in SSc-associated PAH (28). However, our data demonstrate that the increase in GDF-15 levels is not specific to PAH, but is also observed in patients with ILD, and may thus reflect a more general role in the fibrotic process.…”

contrasting

confidence: 59%

Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Lambrecht

Smith

Wilde

et al. 2014

Arthritis & Rheumatology

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ObjectiveTransforming growth factor β superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF‐15) is a distant member of this family. We undertook this study to evaluate the role of GDF‐15 in SSc pathogenesis.MethodsA longitudinal prospective cohort of SSc patients was screened for serum GDF‐15 levels using enzyme‐linked immunosorbent assay, and associations with clinical data were analyzed. In vitro stimulation experiments were performed on lung fibroblasts. The role of GDF‐15 in fibrosis development in vivo was evaluated in the bleomycin lung fibrosis model in GDF‐15–deficient mice.ResultsGDF‐15 was measured at baseline in serum samples from 119 SSc patients. An increase in GDF‐15 levels was observed in patients classified as having no skin involvement, those with limited cutaneous SSc, and those with diffuse cutaneous SSc. Moreover, baseline serum GDF‐15 levels correlated strongly with disease activity and extent of organ involvement, particularly clinical symptoms of lung fibrosis, including impact on lung function at prospective followup. This was mimicked in the bleomycin model of SSc, in which animals exposed to bleomycin had elevated expression levels of GDF‐15 in lung tissue. Lung fibroblasts isolated from GDF‐15–deficient mice showed reduced induction of interleukin‐6 and CCL2 upon bleomycin stimulation. Surprisingly, no differences in fibrosis development were observed between wild‐type and GDF‐15–deficient animals.ConclusionAn intriguing profile of serum GDF‐15 levels was found in SSc patients. GDF‐15 expression is induced during fibrosis development and markedly correlates with lung function impairment in this disease. The protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo.

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“…A novel biomarker in the evaluation of iPAH and SSc-PAH is growth differentiation factor 15 (GDF-15) (61,62). GDF-15 is a member of the transforming growth factor ␤ "super family" of cytokines and is integral to cell growth and differentiation, cell-cell signaling, and apoptosis regulation.…”

Section: Additional Studies That May Be Useful Inmentioning

confidence: 99%

“…GDF-15 levels correlate directly with PAP and the FVC%/DLCO% ratio and are associated with reduced survival. Interestingly, there is increased expression of GDF-15 protein in lung tissue of patients with SSc-PAH, perhaps implicating it in the pathobiology of the disease (61). Further studies are needed to determine whether GDF-15 can be useful as a screening tool for SSc-PAH.…”

Section: Additional Studies That May Be Useful Inmentioning

confidence: 99%

Practical approach to screening for scleroderma‐associated pulmonary arterial hypertension

Fischer¹,

Bull²,

Steen³

2012

Arthritis Care & Research

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Increased Expression of Growth Differentiation Factor-15 in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Cited by 65 publications

References 26 publications

Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Sustained Elevation of Circulating Growth and Differentiation Factor-15 and a Dynamic Imbalance in Mediators of Muscle Homeostasis Are Associated With the Development of Acute Muscle Wasting Following Cardiac Surgery*

Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Practical approach to screening for scleroderma‐associated pulmonary arterial hypertension

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