Growth Differentiation Factor 11 Research Articles

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation

BackgroundDiabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism.Methods and resultsMice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα).ConclusionThese findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

GDF11 improves hippocampal neurogenesis and cognitive abilities in diabetic mice by reducing neural inflammation

BackgroundThe cognitive decline associated with type 2 diabetes (T2D) is often attributed to compromised hippocampal neurogenesis and exacerbated neural inflammation. This study investigates the therapeutic potential of growth differentiation factor 11 (GDF11) in reversing these neurodegenerative processes in diabetic mice. ResultWe utilized a murine model of T2D and examined the effects of GDF11 on learning, memory, neurogenesis, and neuroinflammatory markers. Our results indicate that diabetic mice exhibit significant deficits in cognitive function, mirrored by reduced hippocampal neurogenesis and increased neuroinflammation. Chronic administration of GDF11 was observed to significantly enhance cognitive abilities, as evidenced by improved performance in learning and memory tasks. Concurrently, GDF11 treatment restored neural activity and promoted the regeneration of new neurons within the hippocampus. Inflammatory profiling revealed a reduction in neuroinflammatory markers, which was further supported by reduced microglia numbers. To delineate the role of neuroinflammation, we pharmacologically depleted microglia, leading to a restoration of neurogenesis and cognitive functions in diabetic mice. ConclusionThese findings endorse the hypothesis that GDF11 exerts its beneficial effects by modulating neuroinflammatory pathways. Consequently, GDF11 represents a promising intervention to ameliorate diabetes-induced cognitive impairments and neural degeneration through its anti-inflammatory properties.

GDF11 inhibits the malignant progression of hepatocellular carcinoma via regulation of the mTORC1‑autophagy axis.

Hepatocellular carcinoma (HCC) is a common malignant tumor, which is associated with a poor prognosis and high mortality rate. It is well known that growth differentiation factor 11 (GDF11) acts as a tumor suppressor in various types of cancer, including HCC. The present study aimed to determine the tumor-suppressive properties of GDF11 in HCC and to assess the intrinsic mechanisms. In the present study, the human hepatoma cell line Huh-7 was transfected with the GDF11 overexpression plasmid (Oe-GDF11) for gain-of-function experiments to investigate the effects of GDF11 on the biological behaviors of HCC cells, including proliferation, colony formation, apoptosis, cell cycle arrest, migration, invasion, epithelial-mesenchymal transition (EMT) and angiogenesis. The proliferation, colony formation, apoptosis, cell cycle, migration, invasion and angiogenesis of HCC cells were assessed by CCK-8, EdU staining, colony formation, flow cytometry, wound healing, Transwell and tube formation assays, respectively. Apoptosis-, cell cycle-, EMT-related key factors were also determined by western blot assay. Furthermore, Oe-GDF11-transfected Huh-7 cells were treated with the mammalian target of rapamycin (mTOR) activator MHY1485 for rescue experiments to explore whether GDF11 could exert antitumor effects against HCC via mediating the mTOR complex 1 (mTORC1)-autophagy axis. In the present study, GDF11 was verified to be lowly expressed in HCC cells. Overexpression of GDF11 inhibited the proliferation, colony formation, migration, invasion, EMT and angiogenesis of HCC cells, and facilitated the apoptosis and cell cycle arrest of HCC cells. Additionally, it was verified that overexpression of GDF11 inactivated the mTORC1 signaling pathway to enhance autophagy in HCC cells. Treatment with the mTOR activator MHY1485 partially reversed the tumor-suppressive effects of GDF11 overexpression on HCC. In conclusion, GDF11 may exert tumor-suppressive properties in HCC cells through inactivating the mTORC1 signaling pathway to strengthen autophagy.

Oncogenic miR-106b-5p promotes cisplatin resistance in triple-negative breast cancer by targeting GDF11.

Cytoplatin (CDDP) is a standard treatment for triple-negative breast cancer (TNB), but patient resistance to CDDP limits its efficacy. A growing study confirms that microRNAs (miRNAs) are significantly important in breast cancer, especially TNBC. This research was carried out to examine the function of miR-106b-5p in CDDP resistance of TNBC as well as the downstream mechanism. The miR-106b-5p and growth-differentiation factor 11 (GDF11) expressions in the tissues from TNBC patients and CDDP-treated TNBC cell lines were measured by RT-qPCR. Thereafter, cell proliferation and migration in the presence of CDDP treatment were evaluated via CCK-8 and Transwell assays in the TNBC cells. A xenograft mice model was also established to verify the miR-106b-5p silencing effect on the growth of CDDP resistance TNBC cells in vivo. Luciferase reporter experiments were performed to predict the relationship between miR-106b-5p and GDF11 expression. The results showed that miR-106b-5p was upregulated in the TNBC tumor cells and TNBC cells treated with CDDP and knockdown of this caused inhibition of the TNBC cell lines' proliferation, migration and suppressed the growth of the TNBC xenografted tumors, in the presence of CDDP treatment. In addition, it was observed that miR-106b-5p can bind to GDF11; as a result in the TNBC tissues and CDDP-treated TNBC cell lines the down-regulation of GDF11 was observed. Moreover, GDF11 silencing promoted CDDP-treated TNBC cell lines' proliferation and migration and reversed the interference effect of miR-106b-5p. MiR-106b-5p was upregulated in TNBC and this upregulation may promote CDDP resistance of the TNBC cells by targeting GDF11 and inhibiting its expression.

Tissue Expression of Growth Differentiation Factor 11 in Patients with Breast Cancer.

Protein growth differentiation factor 11 (GDF11) plays crucial roles in cellular processes, including differentiation and development; however, its clinical relevance in breast cancer patients is poorly understood. We enrolled 68 breast cancer patients who underwent surgery at our hospital and assessed the expression of GDF11 in tumorous, ductal carcinoma in situ (DCIS), and non-tumorous tissues using immunohistochemical staining, with interpretation based on histochemical scoring (H-score). Our results indicated higher GDF11 expressions in DCIS and normal tissues compared to tumorous tissues. In addition, the GDF11 H-score was lower in the patients with a tumor size ≥ 2 cm, pathologic T3 + T4 stages, AJCC III-IV stages, Ki67 ≥ 14% status, HER2-negative, and specific molecular tumor subtypes. Notably, the patients with triple-negative breast cancer exhibited a loss of GDF11 expression. Spearman correlation analysis revealed associations between GDF11 expression and various clinicopathological characteristics, including tumor size, stage, Ki67, and molecular subtypes. Furthermore, GDF11 expression was positively correlated with mean corpuscular hemoglobin concentration and negatively correlated with neutrophil count, as well as standard deviation and coefficient of variation of red cell distribution width. These findings suggest that a decreased GDF11 expression may play a role in breast cancer pathogenesis.

Correlation between serum growth differentiation factor 11 level and severity of coronary artery disease in patients with acute myocardial infarction

Objective: To investigate the correlation between serum growth differentiation factor 11 (GDF11) level and coronary artery lesions in patients with ST-segment elevation myocardial infarction (STEMI), and the predictive efficacy of nomogram risk prediction model based on GDF11 combined with traditional risk factors on the occurrence of STEMI. Methods: This study was a retrospective cross-sectional study. Patients hospitalized in the Department of Cardiology of the 904th Hospital of Joint Logistic Support Force of People's Liberation Army of China from 2016 to 2018 were selected and divided into control group and STEMI group. The demographic data, blood lipid level, laboratory indicators of blood and GDF11 level were collected. Logistic regression analysis screened out independent correlated factors for the occurrence of STEMI. Spearman correlation analysis clarified the correlation of each indicator with the SYNTAX or Gensini scores. A nomogram risk prediction model for the risk of STEMI occurrence and the receiver operating characteristic curve was used to compare the prediction efficiency of each model. Results: A total of 367 patients were enrolled, divided into control group (n=172) and STEMI group (n=195), age (66.5±11.8), male 222 (60.49%). The serum GDF11 level of STEMI group was significantly lower than that of the control group (36.20 (16.60, 70.75) μg/L vs. 85.00 (53.93, 117.10) μg/L, P<0.001). The results of multivariate logistic regression analysis showed serum GDF11(OR=0.98, 95%CI: 0.97-0.99) and traditional independent risk factors such as smoking, diabetes, C-reactive protein, homocysteine, lipoprotein (a) and apolipoprotein A1/B were independent correlate factors for the occurrence of STEMI (P<0.05). Spearman correlation analysis showed that serum GDF11 was negatively correlated with SYNTAX score and Gensini score (P<0.05). The nomogram model constructed by serum GDF11 combined with traditional independent risk factors (AUC=0.85, 95%CI: 0.81-0.89) had better predictive value for the occurrence of STEMI than the traditional nomogram model constructed by independent risk factors(AUC=0.80, 95%CI:0.75-0.84) or serum GDF11 (AUC=0.76, 95%CI: 0.72-0.81), all P<0.01. Conclusions: Serum GDF11 is an independent correlate factor in the occurrence of STEMI and is negatively correlated with the severity of coronary artery lesions in patients with STEMI. The nomogram model constructed based on GDF11 combined with traditional risk factors can be a good predictor for the occurrence of STEMI.

GDF11 level and its effect on prognosis in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the proliferation of CD34 positive self-renewing malignant hematopoietic stem cells. Previous studies have shown that the transforming growth factor beta (TGFβ) pathway plays a role in AML pathogenesis, especially by affecting the microenvironment. Growth differentiation factor 11 (GDF11) is a member of the TGFβ superfamily, involved in embryological development and known as rejuvenating factor. In this study, our aim was to determine the serum GDF11 level in patients with AML, to compare it with the control group, to determine its relationship with follistatin, vimentin, and E-cadherin levels, and to determine whether GDF11 influences AML prognosis. Serum GDF11, vimentin, follistatin, and E-cadherin levels of newly diagnosed or relapsed/refractory AML patients and age- and gender-matched control group were measured by enzyme-linked immunosorbent assay. Serum GDF11 level was higher in the patient group (263.87 ± 126.54 ng/L) compared to the control group (211.54 ± 61.47 ng/L; p = 0.035). GDF11 level did not change according to age, gender, hemoglobin level, and bone marrow blast rate. No correlation was found between GDF11 level, response rates, and survival status of the patients. A positive correlation was detected between GDF11, E-cadherin, and vimentin levels. As a conclusion, increased serum GDF11 levels in AML patients may be linked to the regeneration ability of leukemic stem cells. There is a need for studies investigating GDF11 expression in myeloblasts.

GDF11: An emerging therapeutic target for liver diseases and fibrosis.

Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.

Myokines: metabolic regulation in obesity and type 2 diabetes

Abstract Skeletal muscle plays a vital role in the regulation of systemic metabolism, partly through its secretion of endocrine factors which are collectively known as myokines. Altered myokine levels are associated with metabolic diseases, such as type 2 diabetes (T2D). The significance of interorgan crosstalk, particularly through myokines, has emerged as a fundamental aspect of nutrient and energy homeostasis. However, a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major challenge. In this review, we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades, namely interleukin 6 (IL-6), irisin, myostatin (MSTN), growth differentiation factor 11 (GDF11), fibroblast growth factor 21 (FGF21), apelin, brain-derived neurotrophic factor (BDNF), meteorin-like (Metrnl), secreted protein acidic and rich in cysteine (SPARC), β-aminoisobutyric acid (BAIBA), Musclin, and Dickkopf 3 (Dkk3). Related to these, we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and disease. Despite significant advancements in myokine research, many myokines remain challenging to measure accurately and investigate thoroughly. Hence, new research techniques and detection methods should be developed and rigorously tested. Therefore, developing a comprehensive perspective on myokine biology is crucial, as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.

Growth differentiation factor-11 upregulates matrix metalloproteinase 2 expression by inducing Snail in human extravillous trophoblast cells

The human extravillous trophoblast (EVT) cell invasion is an important process during placentation. Although the placenta is normal tissue, the EVT cells exhibit some features common to cancer cells, including high migratory and invasive properties. Snail and Slug are transcription factors that mediate the epithelial-mesenchymal transition (EMT), a crucial event for cancer cell migration and invasion. It has been shown that GDF-11-induced matrix metalloproteinase 2 (MMP2) expression is required for EVT cell invasion. Whether GDF-11 can regulate Snail and Slug expression in human EVT cells remains unknown. If it does, the involvement of Snail and Slug in GDF-11-induced MMP2 expression and EVT cell invasion must also be defined. In the present study, using the immortalized human EVT cell line, HTR-8/SVneo, and primary cultures of human EVT cells as experimental models, our results show that GDF-11 upregulates Snail and Slug expression. ALK4 and ALK5 mediate the stimulatory effects of GDF-11 on Snail and Slug expression. In addition, we demonstrate that SMAD2 and SMAD3 are required for the GDF-11-upregulated Snail expression, while only SMAD3 is involved in GDF-11-induced Slug expression. Moreover, our results reveal that Snail mediates GDF-11-induced MMP2 expression and cell invasion but not Slug. This study increases our understanding of the biological function of GDF-11 in human EVT cells and provides a novel mechanism for regulating MMP2 and EVT cell invasion.

GDF11 mitigates high glucose-induced cardiomyocytes apoptosis by inhibiting the ALKBH5-FOXO3-CDR1as/Hippo signaling pathway

Diabetic cardiomyopathy remains a formidable health challenge with a high mortality rate and no targeted treatments. Growth differentiation factor 11 (GDF11) has shown promising effects on cardiovascular diseases; however, its role and the underlying mechanism in regulating diabetic cardiomyopathy remain unclear. In this study, we developed mouse models of diabetic cardiomyopathy using leptin receptor-deficient (db/db) mice and streptozocin-induced C57BL/6 mice. The diabetic cardiomyopathy model mice exhibited apparent structural damage in cardiac tissues and a significant increase in the expression of apoptosis-related proteins. Notably, we observed a significant decreased expression of GDF11 in the myocardium of mice with diabetic cardiomyopathy. Moreover, GDF11 cardiac-specific knock-in mice (transgenic mice) exhibited improved cardiac function and reduced apoptosis. Moreover, exogenous administration of GDF11 mitigated high glucose-induced cardiomyocyte apoptosis. Mechanistically, we demonstrated that GDF11 alleviated high glucose-induced cardiomyocytes apoptosis by inhibiting the activation of the alkylation repair homolog 5 (ALKBH5)-forkhead box group O3a (FOXO3)-cerebellar degeneration-related protein 1 transcript (CDR1as)/Hippo signaling pathway. Consequently, this novel mechanism effectively counteracted myocardial cell apoptosis, providing valuable insights into potential therapeutic strategies for clinical diabetic cardiomyopathy.

Growth differentiation factor 11 suppresses intrahepatic inflammation via restricting NLRP3 inflammasome activation in LPS-induced liver injury.

Growth differentiation factor 11 (GDF11) is reported as a member of TGF-β superfamily, which plays a key negative role in various tissue inflammation. However, the specific effect of GDF11 on infectious acute liver injury remains unknown. The current study is designed to certify the role of GDF11 both in LPS-induced RAW 264.7 cell line and rodent model of acute liver injury (ALI) and further investigate its molecular mechanism of inflammatory regulation. In vitro, LPS was used to stimulate the inflammatory activation of RAW 264.7 cells and then recombinant GDF11 (rGDF11) was used to treat the cells. In vivo, we injected LPS and rGDF11 in abdomen of mouse. The inflammatory indexes, GDF11 level, NLRP3 level, liver tissue injury, and liver function were examined using qRT-PCR, western blot, ELISA, IHC, IF and HE staining, respectively. Supplement of GDF11 protected the histology and function of liver tissue in LPS-induced ALI mice, in which the level of AST, ALT and TBiL associated with tissue damage were reduced after ALI. Moreover, increased GDF11 in RAW 264.7 cells and ALI mice reduced the expressions of COX-2, TNF-α, IL-1β, and IL-6 via inhibiting NLRP3 inflammasome activation, suggesting the anti-inflammatory role of GDF11 in ALI. Besides, owing to the protective role of GDF11, the apoptotic degree in liver after LPS insult was attenuated, such as the reduced c-caspase-3 and annexin-V expressions. The results indicate that overexpression of GDF11 plays an antagonistic role in LPS-induced inflammatory response after ALI. Therefore, GDF11 may become a promising target for preventing infectious acute liver injury.

The regulatory effect of growth differentiation factor 11 on different cells.

Growth differentiation factor 11 (GDF11) is one of the important factors in the pathophysiological process of animals. It is widely expressed in many tissues and organs of animals, showing its wide biological activity and potential application value. Previous research has demonstrated that GDF11 has a therapeutic effect on various diseases, such as anti-myocardial aging and anti-tumor. This has not only sparked intense interest and enthusiasm among academics but also spurred some for-profit businesses to attempt to develop GDF11 as a medication for regenerative medicine or anti-aging application. Currently, Sotatercept, a GDF11 antibody drug, is in the marketing application stage, and HS-235 and rGDF11 are in the preclinical research stage. Therefore, we believe that figuring out which cells GDF11 acts on and its current problems should be an important issue in the scientific and commercial communities. Only through extensive, comprehensive research and discussion can we better understand the role and potential of GDF11, while avoiding unnecessary risks and misinformation. In this review, we aimed to summarize the role of GDF11 in different cells and its current controversies and challenges, providing an important reference for us to deeply understand the function of GDF11 and formulate more effective treatment strategies in the future.

Plasma rejuvenation factor GDF11 associates with amyloid‐related cognitive decline in older adults across the Alzheimer’s Disease spectrum

AbstractBackgroundThrough studies of animal heterochronic parabiosis (fusion of juvenile and older adult animal circulatory systems), growth differentiation factor 11 (GDF11) has been identified as a blood rejuvenation factor that can promote neurogenesis, vascular remodeling, and memory improvement in the presence of age‐related declines. However, it is unknown whether GDF11’s associations with cognitive and neural outcomes translate to humans. We assessed the relationship between plasma GDF11, cerebral amyloid pathology, and cognitive performance in older adults across the Alzheimer’s disease (AD) spectrum.MethodParticipants were 71 older adults from the UCSF Memory and Aging Center who ranged in age from 63 to 93 (Meanage = 79.5; Meanedu = 17.5, 66 cognitively unimpaired, 56% women, 38% amyloid PET positive) and completed blood draws with plasma analyzed on Somascan (version 4.1), neuropsychological evaluations, and amyloid PET scans (18‐AV‐45). Cognition was operationalized as a of validated tests of memory and executive function. Pearson’s correlations examined interrelationships among plasma GDF11, cognition, and amyloid PET centiloids. To determine whether plasma GDF11 moderated the effects of amyloid on cognition, linear regression examined cognition as a function of GDF11, amyloid, and their interaction, controlling for age, sex, and education.ResultHigher amyloid PET centiloids correlated with worse cognition (r = ‐0.20, p = 0.09) and lower levels of GDF11 (r = ‐0.15, p = 0.20), though relationships did not reach statistical significance. GDF11 also did not strongly univariately correlate with cognition (r = ‐0.07, p = 0.59). However, there was a significant interaction between GDF11 and amyloid PET centiloids on cognition (β = 0.55, 95% CI = 0.15, 0.95, p = 0.008) such that the negative relationship between amyloid PET centiloids and cognition was significantly in participants with higher levels of GDF11.ConclusionGDF11 is a blood‐based rejuvenation factor that supports neurogenesis and cognition in animal models and attenuates the association between higher amyloid burden and worse cognition in cognitively unimpaired older adults. These results coupled with prior findings provide translational evidence that GDF11 supports brain resilience and further examination of GDF11 as a therapeutic target for Alzheimer’s disease is warranted.

GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

Circulating growth differentiation factor 11 exacerbates myocardial injury in mice and associates with increased infarct size in humans

Abstract Background The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a TGF-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. Methods Young (3-4 months) and old (22-24 months) C57Bl/6 mice were subjected to either systemic recombinant GDF11 (rGDF11; 0.1 mg/kg BW daily) or control treatment over 30 days before myocardial ischaemia-reperfusion (I/R) injury was induced. Dissected hearts underwent in-depth profiling that ranged from histological workup and the assessment of inflammatory pathways to cardiomyocyte viability testing and IPA-guided -omics. Key regulatory mechanisms were studied in vitro using human adult stromal cardiac-specific mesenchymal cells (cMSCs) and HL-1 cardiomyocytes. By harnessing liquid chromatography–tandem mass spectrometry (LC-MS/MS), plasma levels of GDF11/MSTN were determined in prospectively recruited patients with MI and the independent association with myocardial infarct size was estimated using hierarchical regression models. Results In contrast to endogenous Mstn, myocardial Gdf11 mRNA expression levels declined upon ageing, and were further reduced following I/R injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by rGDF11 delivery prior to myocardial I/R augmented rather than reduced infarct size in mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. By applying a targeted transcriptomics approach on dissected hearts subjected to I/R, we identified the mesenchymal marker Nkx2-5 to be blunted upon rGDF11 supplementation, pointing toward a cMSC-mediated mechanism. Accordingly, human cMSCs exposed to high rGDF11 in vitro showed similar reductions in NKX2-5 expression levels, coinciding with diminished anti-apoptotic effects conferred by resident cMSCs on HL-1 cardiomyocytes. Finally, by harnessing a highly-specific LC–MS/MS based assay, we show that in patients with MI receiving contemporary management circulating GDF11 but not MSTN levels inclined with age. Moreover, circulating GDF11 emerged as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. Notably, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event. Conclusions Our data challenge the initially reported rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice by impinging on the cardioprotective effects of resident cMSCs. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of endogenous cardioprotective mechanisms and thus poor outcomes post-MI.

GDF11 mediates H2S to prevent chronic stress-induced cognitive impairment by reducing hippocampal NLRP3/caspase-1-dependent pyroptosis

BackgroundWe previously revealed that hydrogen sulfide (H2S) attenuates chronic stress-induced cognitive impairment, but the underlying mechanism needs to be further clarified. Growth differentiation factor 11 (GDF11) plays an important regulatory role in cognitive function and that hippocampal NLRP3/caspase-1-mediated pyroptosis contributes to the pathogenesis of cognitive impairment. Hence, this research aimed to explore whether promoting GDF11 levels and suppressing hippocampal NLRP3/caspase-1-mediated pyroptosis mediate H2S to alleviate chronic stress-induced cognitive impairment. MethodsSprague–Dawley rats were subjected to unpredictable chronic mild stress lasting four weeks to establish an animal model of chronic stress-induced cognitive impairment. Behavioral performance was assessed by the Y-maze test and the novel object recognition test. The expression levels of proteins were analyzed by Western blot analysis. The levels of IL-1β and IL-18 in the hippocampus were measured by ELISA. ResultsNaHS upregulated the expression of GDF11 in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed rats. Silencing GDF11 blocked NaHS-improved cognitive impairment in CUMS-exposed rats, according to the Y-maze test and the novel object recognition test. Furthermore, NaHS mitigated NLRP3/caspase-1-mediated pyroptosis in the hippocampus of CUMS-exposed rats and this effect was reversed by silencing GDF11. Moreover, overexpression of GDF11 alleviated CUMS-induced cognitive impairment and NLRP3/caspase-1-mediated hippocampal pyroptosis. ConclusionsGDF11 mediates H2S to attenuate chronic stress-induced cognitive impairment via inhibiting hippocampal NLRP3/caspase-1-mediated pyroptosis.

Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells.

Growth differentiation factor 11 (GDF11) is a putative systemic rejuvenation factor. In this study, we characterized the mechanism by which GDF11 reversed aging of mesenchymal stem cells (MSCs). In culture, aged MSCs proliferate slower and are positive for senescence markers senescence-associated β-galactosidase and P16ink4a . They have shortened telomeres, decreased GDF11 expression, and reduced osteogenic potential. GDF11 can block MSC aging in vitro and reverse age-dependent bone loss in vivo. The antiaging effect of GDF11 is via activation of the Smad2/3-PI3K-AKT-mTOR pathway. Unexpectedly, GDF11 also upregulated a DNA demethylase Tet2, which served as a key mediator for GDF11 to autoregulate itself via demethylation of the GDF11 promoter. Mutation of Tet2 facilitates MSC aging by blocking GDF11 expression. Mutagenesis of Tet2-regulated CpG sites also blocks GDF11 expression, leading to MSC aging. Together, a novel mutual regulatory relationship between GDF11 and an epigenetic factor Tet2 unveiled their antiaging roles.

SAT267 BMP4, GDF11 And TGFβ2 Repress Adrenal Cell Cortisol Production By Blocking CYP17A1 And CYP11B1 Expression

Abstract Disclosure: E.C. Fischbach: None. A. Lopez: None. M. Ullenbruch: None. J. Rege: None. W.E. Rainey: None. Introduction: The adrenal cortex is responsible for the biosynthesis of multiple steroid hormones that regulate electrolyte and carbohydrate balance. Cortisol, the principal glucocorticoid in humans, is primarily produced in the middle zone of the cortex known as the zona fasciculata (ZF). The enzymes responsible for cortisol biosynthesis include cytochrome P450c17 (17α-hydroxylase), encoded by CYP17A1 and cytochrome P450c11 (11β-hydroxylase), encoded by CYP11B1. Several paracrine/autocrine regulators, including members of the transforming growth factor beta (TGFβ) superfamily, have been implicated in controlling adrenocortical cell homeostasis and steroid hormone production. Previously, we reported a bone morphogenetic protein 4 (BMP4) expression gradient in the adrenal cortex with higher levels in the zona glomerulosa (ZG) and outer ZF compared to the zona reticularis (ZR). In this study, we sought to compare adrenal expression of members of the TGFβ family including BMP4, growth differentiation factor 11 (GDF11), and transforming growth factor beta 2 (TGFβ2), and determine their effect on adrenal cell cortisol biosynthesis. Methods: Growth factor mRNA levels were studied using microarray analysis of laser captured ZG, ZF and ZR from human adrenals. The adrenal cell line, HAC15 was used to determine the effects of the TGFβ family members alone and in combination. Output measures included cell cortisol production and mRNA levels of steroidogenic enzymes using ELISA and quantitative RT-PCR, respectively. Results: Microarray analysis indicated higher mRNA levels of BMP4, GDF11 and TGFβ2 in the ZG compared with the ZF and ZR regions of the adrenal. Treatment of HAC15 cells with either BMP4 (50 ng/mL), GDF11 (50 ng/mL) or TGFβ2 (10 ng/mL) significantly inhibited cortisol production, as well as CYP11B1 and CYP17A1 mRNA levels. The inhibition was observed under basal and forskolin-stimulated conditions. Furthermore, the inhibitory effects on cortisol production and enzyme expression were additive when factors were added together. Summary: Overall, our findings suggest that the human adrenal has a gradient of multiple members of the TGFβ family. The additive action of these growth factors on adrenal cell differentiation may explain, in part, the inability of the ZG to produce cortisol and its low expression of CYP11B1 and CYP17A1. Presentation: Saturday, June 17, 2023

Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.

The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.