C1q/Tumor Necrosis Factor-Related Protein-3, a Newly Identified Adipokine, Is a Novel Antiapoptotic, Proangiogenic, and Cardioprotective Molecule in the Ischemic Mouse Heart

Yi, Wei; Sun, Yang; Yuan, Yuexing; Lau, Wayne Bond; Zheng, Qijun; Wang, Xiaoliang; Wang, Yajing; Shang, Xianwen; Gao, Erhe; Koch, Walter J.; Ma, Xin‐Liang

doi:10.1161/circulationaha.112.099937

Cited by 154 publications

(172 citation statements)

References 30 publications

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“…41 C1q and tumor necrosis factorrelated protein 9 secreted by fat cells is also cardioprotective, proangiogenic, and antiapoptotic, 42 and increased C1q and tumor necrosis factor-related protein 9 could restore cardiac function, attenuate cardiomyocyte apoptosis, and increase neovascularization in hypoxia-induced cardiomyocyte injury. 43 Therefore, it is likely that intramyocardial adipocytes in the normal heart exert a protective role for cardiomyocytes and coronary vessels through paracrine mechanism, which merits further investigation in the future. However, excessive adipocytes might also be associated with cardiovascular diseases, such as arrhythmogenic right ventricular cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Endocardium Contributes to Cardiac Fat

Zhang

Liu

et al. 2016

Circulation Research

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Rationale: Unraveling the developmental origin of cardiac fat could offer important implications for the treatment of cardiovascular disease. The recent identification of the mesothelial source of epicardial fat tissues reveals a heterogeneous origin of adipocytes in the adult heart. However, the developmental origin of adipocytes inside the heart, namely intramyocardial adipocytes, remains largely unknown. Objective: To trace the developmental origin of intramyocardial adipocytes. Methods and Results: In this study, we identified that the majority of intramyocardial adipocytes were restricted to myocardial regions in close proximity to the endocardium. Using a genetic lineage tracing model of endocardial cells, we found that Nfatc1 + endocardial cells contributed to a substantial number of intramyocardial adipocytes. Despite the capability of the endocardium to generate coronary vascular endothelial cells surrounding the intramyocardial adipocytes, results from our lineage tracing analyses showed that intramyocardial adipocytes were not derived from coronary vessels. Nevertheless, the endocardium of the postnatal heart did not contribute to intramyocardial adipocytes during homeostasis or after myocardial infarction. Conclusions: Our in vivo fate-mapping studies demonstrated that the developing endocardium, but not the vascular endothelial cells, gives rise to intramyocardial adipocytes in the adult heart.

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Section: Discussionmentioning

confidence: 99%

Endocardium Contributes to Cardiac Fat

Zhang

Liu

et al. 2016

Circulation Research

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“…It should be noted that an absence of overt metabolic phenotypes seen in the Ctrp3-KO mice does not, in principle, negate its potential beneficial metabolic properties when recombinant protein is administered in vivo, as illustrated by its ability to markedly reduce hepatic triglyceride levels in obese WT mice with existing liver steatosis (40). Elevating plasma levels of CTRP3 can also have beneficial cardiac effects in conditions of ischemic heart attack (69). There are obvious limitations in our current study in which we employ a whole body KO mouse model deficient in CTRP3 protein throughout development and in adult animals.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond metabolic control, recent studies have also shown that CTRP3 has anti-inflammatory properties (22,23,48) as well as cardioprotective effects in mouse models of ischemic heart attack (69). Interestingly, overexpressing CTRP3 in mice also promotes phosphate-induced vascular smooth muscle cell calcification (73).…”

mentioning

confidence: 99%

CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice

Wolf

Lei

Zhi

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Wolf RM, Lei X, Yang Z, Nyandjo M, Tan SY, Wong GW. CTRP3 deficiency reduces liver size and alters IL-6 and TGF␤ levels in obese mice. Am J Physiol Endocrinol Metab 310: E332-E345, 2016. First published December 15, 2015; doi:10.1152/ajpendo.00248.2015.-C1q/TNF-related protein 3 (CTRP3) is a secreted metabolic regulator whose circulating levels are reduced in human and rodent models of obesity and diabetes. Previously, we showed that CTRP3 infusion lowers blood glucose by suppressing gluconeogenesis and that transgenic overexpression of CTRP3 protects mice against diet-induced hepatic steatosis. Here, we used a genetic loss-of-function mouse model to further address whether CTRP3 is indeed required for metabolic homeostasis under normal and obese states. Both male and female mice lacking CTRP3 had similar weight gain when fed a control low-fat (LFD) or high-fat diet (HFD). Regardless of diet, no differences were observed in adiposity, food intake, metabolic rate, energy expenditure, or physical activity levels between wild-type (WT) and Ctrp3-knockout (KO) animals of either sex. Contrary to expectations, loss of CTRP3 in LFD-or HFD-fed male and female mice also had minimal or no impact on whole body glucose metabolism, insulin sensitivity, and fasting-induced hepatic gluconeogenesis. Unexpectedly, the liver sizes of HFD-fed Ctrp3-KO male mice were markedly reduced despite a modest increase in triglyceride content. Furthermore, liver expression of fat oxidation genes was upregulated in the Ctrp3-KO mice. Whereas the liver and adipose expression of profibrotic TGF␤1, as well as its serum levels, was suppressed in HFD-fed KO mice, circulating proinflammatory IL-6 levels were markedly increased; these changes, however, were insufficient to affect systemic metabolic outcome. We conclude that, although it is dispensable for physiological control of energy balance, CTRP3 plays a previously unsuspected role in modulating liver size and circulating cytokine levels in response to obesity. adipokine; C1q/tumor necrosis factor-related protein; C1q/tumor necrosis factor; fatty liver; obesity; diabetes THE C1Q/TNF-RELATED PROTEIN (CTRP) family comprises 15 secreted plasma proteins of the C1q family, the first seven of which were identified initially on the basis of sequence homology to the globular C1q domain of adiponectin (66); additional members were subsequently described (6, 43, 49, 59 -61, 64, 65). Recent functional studies demonstrated important and distinct roles for CTRPs in regulating glucose and/or lipid metabolism in the peripheral tissues (38 -42, 57-60) as well as having a central role in modulating food intake (6, 7) and adipocyte differentiation in culture (61). Unlike adiponectin, whose expression is restricted to adipocytes (47), CTRP family members are much more widely expressed (65, 66); all are conserved throughout vertebrate evolution (50).Multiple in vitro and in vivo approaches have been used to elucidate the biological function of one member, CTRP3, a secreted plasma protein whose circulating levels ...

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“…CTRP3 replenishment improves survival and restores cardiac function after MI and attenuates post-ischemic pathologic remodeling (evidenced by echocardiographic and histologic parameters). 93 Preventing post-MI CTRP3 inhibition or CTRP3 supplementation may aid in the restoration of cardiac function and mitigate heart failure sequelae ( Figure 5). …”

Section: Ctrp3mentioning

confidence: 99%

Role of Adipokines in Cardiovascular Disease

Lau

Ohashi

Wang

et al. 2017

Circ J

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143

101

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Cardiovascular disease (CVD) is the greatest cause of death, accounting for nearly one-third of all deaths worldwide. The increase in obesity rates over 3 decades is widespread and threatens the public health in both developed and developing countries. Obesity, the excessive accumulation of visceral fat, causes the clustering of metabolic disorders, such as type 2 diabetes, dyslipidemia, and hypertension, culminating in the development of CVD. Adipose tissue is not only an energy storage organ, but an active endocrine tissue producing various biologically active proteins known as adipokines. Since leptin, a central regulator of food intake and energy expenditure, was demonstrated to be an adipose-specific adipokine, attention has focused on the identification and characterization of unknown adipokines to clarify the mechanisms underlying obesity-related disorders. Numerous adipokines have been identified in the past 2 decades; most adipokines are upregulated in the obese state. Adipokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and resistin are pro-inflammatory, and exacerbate various metabolic and cardiovascular diseases. However, a small number of adipokines, including adiponectin, are decreased by obesity, and generally exhibit antiinflammatory properties and protective functions against obesity-related diseases. Collectively, an imbalance in the production of pro-and antiinflammatory adipokines in the obese condition results in multiple complications. In this review, we focus on the pathophysiologic roles of adipokines with cardiovascular protective properties.

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C1q/Tumor Necrosis Factor-Related Protein-3, a Newly Identified Adipokine, Is a Novel Antiapoptotic, Proangiogenic, and Cardioprotective Molecule in the Ischemic Mouse Heart

Cited by 154 publications

References 30 publications

Endocardium Contributes to Cardiac Fat

Endocardium Contributes to Cardiac Fat

CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice

Role of Adipokines in Cardiovascular Disease

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