Cardiovascular and Metabolic Regulation by the Adiponectin/C1q/Tumor Necrosis Factor–Related Protein Family of Proteins

Ouchi, Noriyuki; Walsh, Kenneth

doi:10.1161/circulationaha.112.114181

Cited by 45 publications

(36 citation statements)

References 19 publications

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“…The secretomes produced by the heart, collectively known as ‘cardiokines’, are increasingly recognized as essential regulators of cardiac physiology and pathology. The C1q/TNF-related proteins (CTRPs) are a protein family consisting of fifteen (CTRP1-CTRP15) newly identified APN paralogs 8 . We have previously demonstrated that CTRP9 is not a typical adipokine, and actually functions as a cardiokine 9 .…”

Section: Introductionmentioning

confidence: 99%

C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

et al. 2017

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Background Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair post myocardial infarction (MI). C1q/tumor necrosis factor–related protein-9 (CTRP9) is a novel pro-survival cardiokine with significantly downregulated expression after MI. Here, we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection. Methods Mice were subjected to MI and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were employed to uncover the molecular mechanisms of CTRP9. Results Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 or P<0.01 vs. CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9KO heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by ERK1/2-MMP-9 signaling and promotes anti-apoptotic/cell survival via ERK-Nrf2/anti-oxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the above noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes Sod-3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. Conclusion We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK/MMP-9 and ERK/Nrf2 signaling, and upregulation/secretion of anti-oxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.

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Section: Introductionmentioning

confidence: 99%

C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

et al. 2017

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“…2). The expression of other adipokines, adiponectin and C1q/TNF-related protein 9 (CTRP9), which have cardiovascular-and metabolic-protective activities (8,9,(37)(38)(39)(40)(41), was also examined in the myocardial I/R model. Like Sfrp5, the CTRP9 transcript was down-regulated following ischemic myocardial injury in both pericardial and epididymal fat depots (Fig.…”

Section: Resultsmentioning

confidence: 99%

Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury

Nakamura

Sano

Fuster

et al. 2016

Journal of Biological Chemistry

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109

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Wnt signaling has diverse actions in cardiovascular development and disease processes. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow-derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling.Inflammation is widely recognized to be involved in the pathogenesis, severity, and outcome of ischemic heart disease (1). Obesity is thought to contribute to cardiovascular disorders, at least in part, through the systemic release of pro-inflammatory adipokines by dysfunctional white adipose tissue (WAT) 2 (2, 3). Inflammation has complex roles in both adaptive healing process following infarction as well as in the maladaptive processes that contribute to heart failure (4 -7), and the acute healing and eventual outcome of ischemic myocardial injury are dependent upon the appropriately choreographed regulation of numerous pro-and anti-inflammatory modulators. In this regard, immune modulators produced by adipose tissue can either facilitate or impair the myocardial healing process, depending on the status of adipose tissue function and the composition of its inflammatory secretome (3,8,9). Thus, a better understanding of the links between obesity-mediated inflammatory processes and post-infarct remodeling of the heart is warranted.At the cellular level, inflammatory processes are tightly orchestrated by secreted signaling molecules that bind to specific cell surface receptors and activate intracellular signaling pathways. Signaling by Wnt ligands is a major regulator of several biological processes, but its roles in modulating inflammatory responses are relatively understudied. The 19 Wnt family proteins contain cysteine-rich domains and activate signaling by binding to one or more of the 10 frizzled family receptors (10). Wnt signaling can be classified as canonical or a noncanonical (10, 11). Canonical Wnt signaling involves activation of the ␤-catenin signaling pathway. Non-canonical Wnt signaling involves other pathways including planar cell polarity and Ca 2ϩ pathways (10, 12, 13). Wnt3a is the prototypical ligand that induces canonica...

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“…CTRP9 belongs to the recently discovered family of CTRPs, which are paralogs of adiponectin. 11,12 Besides adiponectin, 15 additional family members have so far been identified (CTRP1-15). Among this protein family, CTRP9 exerts by far the highest expression in the heart and can also be found in serum and adipose tissue.…”

Section: Appari Et Al Ctrp9 Promotes Cardiac Hypertrophy 67mentioning

confidence: 99%

C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure

Appari

Breitbart

Brandes

et al. 2017

Circulation Research

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Rationale: Myocardial endothelial cells promote cardiomyocyte hypertrophy, possibly through the release of growth factors. The identity of these factors, however, remains largely unknown, and we hypothesized here that the secreted CTRP9 (C1q-tumor necrosis factor–related protein-9) might act as endothelial-derived protein to modulate heart remodeling in response to pressure overload. Objective: To examine the source of cardiac CTRP9 and its function during pressure overload. Methods and Results: CTRP9 was mainly derived from myocardial capillary endothelial cells. CTRP9 mRNA expression was enhanced in hypertrophic human hearts and in mouse hearts after transverse aortic constriction (TAC). CTRP9 protein was more abundant in the serum of patients with severe aortic stenosis and in murine hearts after TAC. Interestingly, heterozygous and especially homozygous knock-out C1qtnf9 (CTRP9) gene-deleted mice were protected from the development of cardiac hypertrophy, left ventricular dilatation, and dysfunction during TAC. CTRP9 overexpression, in turn, promoted hypertrophic cardiac remodeling and dysfunction after TAC in mice and induced hypertrophy in isolated adult cardiomyocytes. Mechanistically, CTRP9 knock-out mice showed strongly reduced levels of activated prohypertrophic ERK5 (extracellular signal-regulated kinase 5) during TAC compared with wild-type mice, while CTRP9 overexpression entailed increased ERK5 activation in response to pressure overload. Inhibition of ERK5 by a dominant negative MEK5 mutant or by the ERK5/MEK5 inhibitor BIX02189 blunted CTRP9 triggered hypertrophy in isolated adult cardiomyocytes in vitro and attenuated mouse cardiomyocyte hypertrophy and cardiac dysfunction in vivo, respectively. Downstream of ERK5, we identified the prohypertrophic transcription factor GATA4, which was directly activated through ERK5-dependent phosphorylation. Conclusions: The upregulation of CTRP9 during hypertrophic heart disease facilitates maladaptive cardiac remodeling and left ventricular dysfunction and might constitute a therapeutic target in the future.

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Cardiovascular and Metabolic Regulation by the Adiponectin/C1q/Tumor Necrosis Factor–Related Protein Family of Proteins

Cited by 45 publications

References 19 publications

C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury

C1q-TNF-Related Protein-9 Promotes Cardiac Hypertrophy and Failure

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