Immunosuppression of Macrophages Underlies the Cardioprotective Effects of CST (Catestatin)

Ying, Wei; Tang, Kechun; Avolio, Ennio; Schilling, Jan M.; Pasqua, Teresa; Liu, Matthew A.; Cheng, Hongqiang; Gao, Hong; Zhang, Jing; Mahata, Sumana; Ko, Marcia G.; Bandyopadhyay, Gautam; Das, Soumita; Roth, David M.; Sahoo, Debashis; Webster, Nicholas J. G.; Sheikh, Farah; Ghosh, Gourisankar; Patel, Hemal H.; Ghosh, Pradipta; Bogaart, Geert van den; Mahata, Sushil K.

doi:10.1161/hypertensionaha.120.16809

Cited by 38 publications

(56 citation statements)

References 67 publications

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“…The shifts observed in the microbial phyla in this study after treating WT mice with CST are in agreement with the findings of Rabbi et al, who also reported an increase in Bacteroidota and a decrease in Firmicutes, albeit a different route for the administration of CST and dosage, (Rabbi, Munyaka, and Eissa 2017). Low abundance of Bacteroidota, especially Bacteroides/Prevotella have been linked to obesity, and CST-KO mice were described to be insulin resistant and obese besides having elevated blood pressure 13,27 . In contrast, increased Bacteroidetes/Firmicutes ratio has been associated with IBD 28,29 , which is characterized by elevated levels of CST (Muntjewerff et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Catestatin selects for the colonization of antimicrobial-resistant gut bacterial communities

González-Dávila

Schwalbe

Danewalia

et al. 2021

Preprint

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The gut microbiota is in continuous interaction with the innermost layer of the gut, namely the epithelium. Among the various functions of the gut epithelium, is to keep the microbes at bay to avoid overstimulation of the underlying mucosa immune cells. To do so, the gut epithelia secrete a variety of antimicrobial peptides, such as catestatin (CST). As a defense mechanism, gut microbes have evolved antimicrobial resistance mechanisms to counteract the killing effect of the secreted peptides. To this end, we treated wild-type mice and mice with a knockout in the CST coding region of the chromogranin-A gene (CST-KO) with CST for 15 consecutive days. CST treatment was associated with a shift in the diversity and composition of the microbiota in the CST-KO mice. This effect was less prominent in WT mice. Levels of the microbiota-produced short-chain fatty acids, in particular, butyrate and acetate were significantly increased in CST-treated CST-KO mice but not the WT group. Remarkably, both CST-treated CST-KO and WT mice showed a significant increase in microbiota-harboring phosphoethanolamine transferase-encoding genes, which facilitate their antimicrobial resistance. Finally, we show that CST was degraded by Escherichia coli via an omptin-protease and that the abundance of this gene was significantly higher in metagenomic datasets collected from patients with Crohn's disease but not with ulcerative colitis. Overall, this study illustrates how the endogenous antimicrobial peptide, CST, shapes the microbiota composition in the gut and primes further research to uncover the role of bacterial resistance to CST in disease states such as inflammatory bowel disease.

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Section: Discussionmentioning

confidence: 99%

Catestatin selects for the colonization of antimicrobial-resistant gut bacterial communities

González-Dávila

Schwalbe

Danewalia

et al. 2021

Preprint

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“…These findings suggest that the two peptides contribute to the biodefence and inflammatory response in vascular walls. Catestatin and vasostatin-1 induce the anti-inflammatory phenotype and suppress the inflammation in human macrophages [ 19 , 20 , 109 ].…”

Section: Atherosclerosismentioning

confidence: 99%

The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease

Watanabe

2021

IJMS

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Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.

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“…Accordingly, the abovementioned mechanism of ChgA hyperglycosylation (leading to reduced catestatin levels) might operate in essential hypertension as well. Recent preclinical data corroborate that catestatin acts as an autocrine attenuator of cardiac inflammation in hypertension by reducing macrophage inflammation in the heart as catestatin-KO mice did not only develop a hypertensive phenotype, but also showed marked left ventricular hypertrophy, macrophage infiltration of the heart and adrenal glands, as well as elevated levels of proinflammatory cytokines and catecholamines [ 54 ]. This work was the first to show that the immunosuppression of macrophages is a driving mechanism behind the cardioprotective effects of catestatin.…”

Section: Role Of Catestatin In Various Cardiovascular Disordersmentioning

confidence: 90%

Catestatin as a Biomarker of Cardiovascular Diseases: A Clinical Perspective

et al. 2021

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Accounting for almost one-third of the global mortality, cardiovascular diseases (CVDs) represent a major global health issue. Emerging data suggest that most of the well-established mechanistic explanations regarding the cardiovascular pathophysiology are flawed, and cannot fully explain the progression and long-term effects of these diseases. On the other hand, dysregulation of the sympathetic nervous system (SNS) has emerged as an important player in the pathophysiology of CVDs. Even though upregulated SNS activity is an essential compensatory response to various stress conditions, in the long term, it becomes a major contributor to both cardiac dysfunction and vascular damage. Despite the fact that the importance of SNS hyperactivity in the setting of CVDs has been well-appreciated, its exact quantification and clinical application in either diagnostics or therapy of CVDs is still out of reach. Nevertheless, in recent years a number of novel laboratory biomarkers implicated in the pathophysiology of SNS activation have been explored. Specifically, in this review, we aimed to discuss the role of catestatin, a potent physiological inhibitor of catecholamine spillover that offers cardioprotective effects. Limited data indicate that catestatin could also be a reliable indirect marker of SNS activity and it is likely that high CST levels reflect advanced CV disease burden. Consequently, large-scale studies are required to validate these observations in the upcoming future.

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Immunosuppression of Macrophages Underlies the Cardioprotective Effects of CST (Catestatin)

Cited by 38 publications

References 67 publications

Catestatin selects for the colonization of antimicrobial-resistant gut bacterial communities

Catestatin selects for the colonization of antimicrobial-resistant gut bacterial communities

The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease

Catestatin as a Biomarker of Cardiovascular Diseases: A Clinical Perspective

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