Serotonin 5-HT 2B Receptor in Cardiac Fibroblast Contributes to Cardiac Hypertrophy

Abstract

HomeCirculation ResearchVol. 104, No. 1Serotonin 5-HT2B Receptor in Cardiac Fibroblast Contributes to Cardiac Hypertrophy Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSerotonin 5-HT2B Receptor in Cardiac Fibroblast Contributes to Cardiac HypertrophyA New Therapeutic Target for Heart Failure? Kou-Gi Shyu Kou-Gi ShyuKou-Gi Shyu From the Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei; and Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taiwan. Search for more papers by this author Originally published2 Jan 2009https://doi.org/10.1161/CIRCRESAHA.108.191122Circulation Research. 2009;104:1–3Cardiac hypertrophy is often accompanied by cardiac remodeling characterized by loss of cardiac myocytes, interstitial fibroblasts, and collagen deposition, leading to decreased ventricular compliance and an increased risk for heart failure. The mortality for patients with heart failure is still high, although some improvements have been demonstrated in patients with systolic heart failure.1–3 To improve the therapeutic strategy for patients with heart failure, especially diastolic heart failure, further research and investigations to better understand the molecular and biochemical mechanism are needed.Serotonin (5-hydroxytryptamine [5-HT]) affects many physiological functions through the interaction with specific G-coupled membrane receptors, 5-HT receptors. There are 4 classes of 5-HT receptors (5-HT1/5, 5-HT2, 5-HT3, and 5-HT4/6/7).4 Serotonin, via the 5-HT2B receptor, regulates cardiac development and function.5 Transgenic mice with a 5-HT2B receptor gene ablation show embryonic and neonatal death caused by lack of trabeculae in the heart.6 5-HT2B receptors are essential for isoproterenol-induced cardiac hypertrophy, which involves the regulation of interleukin-6, interleukin-1β, and tumor necrosis factor-α cytokine production by cardiac fibroblasts.7 The 5-HT2B receptor has been shown functionally coupled to reactive oxygen species synthesis through NAD(P)H oxidase stimulation in neuronal cells8 and in angiotensin II and isoproterenol-induced cardiac hypertrophy.9 Recently, 5-HT2B receptor blockade has been shown to prevent the cardiac hypertrophy induced by angiotensin II or isoproterenol infusion.9 The 5-HT2B receptor has also been shown to be involved in cardiac hypertrophy by acting directly on cardiac myocytes.10 Serotonin plasma level and serotonin activity are increased in patients with heart failure and in animal studies with cardiac hypertrophy induced by aortic constriction.11 These findings may indicate that serotonin induces cardiac hypertrophy or heart failure through the 5-HT2B receptor.Most of the previous studies on cardiac hypertrophy focus on the molecular and biochemical mechanisms, including neuroendocrine activation, signaling pathways, and even therapeutic strategy in cardiac myocytes.12,13 In this issue of Circulation Research, Jaffré et al14 report novel findings regarding the regulatory mechanisms of the 5-HT2B receptor and local angiotensin II in cardiac fibroblasts. These regulatory mechanisms are required for isoproterenol-dependent cardiac hypertrophy in mice. Expression of 5HT2B receptors in cardiac fibroblasts is required for isoproterenol-induced cardiac hypertrophy. 5HT2B receptors, angiotensin II and angiotensin II type 1 (AT1) receptors are necessary intermediates for isoproterenol-induced cytokine release in adult cardiac fibroblasts. They found a common signal transduction pathway for 5-HT2B receptor– and AT1 receptor–induced cytokine production that requires the transactivation of the epidermal growth factor /ErbB-receptor family via matrix metalloproteinase (MMP)-dependent cleavage of heparin-binding epidermal growth factor. This is an interesting study to address the role of cardiac fibroblasts on adrenergic dependent cytokine production and cardiac hypertrophy through serotonin/angiotensin II. In particular, the generation of mice overexpressing the 5-HT2B receptor only in cardiac myocytes through mating α-MHC-5-HT2B+/− and 5-HT2B−/− is a very good way to demonstrate the importance of noncardiac 5-HT2B receptor. These findings may have important clinical implications because sympathetic activity, 5-HT2B receptor expression, and plasma cytokines were all increased in patients with heart failure. These data clearly indicate that the 5-HT2B receptor in cardiac fibroblasts may represent a new therapeutic target to reduce cardiac pathological hypertrophy and hypertrophy-induced heart failure.The etiology of cardiac hypertrophy is complex, including mechanical stress, several neurohumoral factors (angiotensin II, endothelin, and β-adrenergic agonist, etc). Although Jaffré and colleagues9,14 have demonstrated that a 5-HT2B receptor antagonist could prevent cardiac hypertrophy by isoproterenol or angiotensin II infusion, the effect of a 5-HT2B receptor antagonist on other models of cardiac hypertrophy is not known. The authors used coimmunolocalization and pull-down assay to prove that the AT1 receptor and 5-HT2B receptor form a heterodimeric complex. However, it is still not known whether antagonists of the AT1 receptor, an effective agent to improve systolic heart failure, have the same effect as 5-HT2B receptor antagonists to prevent cardiac hypertrophy. It is also not known whether there is a synergistic effect of combination of 5-HT2B receptor and AT1 receptor antagonists to treat hypertrophy-induced heart failure.Different classes and subtypes of 5-HT receptors may work differently in cardiac myocytes. Jaffré et al did not investigate the role of other 5-HT receptors in their transgenic mice model. Recently, Qvigstad et al15 have reported that rats with acute heart failure develop ventricular inotropic responsiveness to serotonin, mediated through Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT4 receptors. In chronic heart failure, serotonin increases ventricular inotropic response through 5-HT4 receptor.16 5-HT4 receptor blockers reduce cardiac energy consumption in chronic heart failure. Using 5-HT2B receptor antagonists may counteractively increase serotonin level, which may increase binding to other 5-HT receptors and induce adverse cardiac effects (Figure). The 5-HT2B receptor increases oxidative stress in cardiac fibroblasts and 5-HT2B receptor blockade reduces the oxidative stress.9 However, recent studies demonstrated that serotonin stimulates cardiac myocyte hypertrophy by receptor independent and receptor-dependent mechanism15 and that serotonin induces cardiac myocytes apoptosis is receptor-independent.17 It has not been reported whether the elevated serotonin by 5-HT2B receptor blockade could have deleterious or neutral effect on cardiac myocytes. Download figureDownload PowerPointSchematic summary of the 5-HT2B receptor on cardiac hypertrophy. The diagram summarizes the interaction between cardiac myocytes and fibroblasts and the effect of the serotonin receptor in cardiac myocytes and fibroblasts, leading to cardiac hypertrophy and possibly heart failure.MMPs, which are important markers for cardiac fibrosis in patients with diastolic heart failure,18 are involved in the downstream signaling of the adrenergic-dependent cardiac hypertrophy reported by Jaffré et al.14 Active fibrotic process that produces increased ventricular stiffness compromising filling may explain the pathophysiology of diastolic heart failure. A primary cause of diastolic heart failure is hypertensive heart disease, which causes cardiac hypertrophy and functional abnormalities. Although MMP inhibitors prevent angiotensin II– and serotonin-induced cytokine release by cardiac fibroblasts, it is not known whether 5-HT2B receptor blockade can reduce MMP content or activity in the cardiac fibroblasts.In summary, Jaffré et al14 clearly demonstrated the requirement of angiotensin II and autocrine stimulation of AT1 receptors interacting with 5-HT2B receptors in cardiac fibroblasts for β-adrenergic–dependent hypertrophic responses. A new target for treatment of heart failure may give new hope for improving prognosis and prolong survival of patients with heart failure. The findings reported by Jaffré et al provide the evidence that the 5-HT2B receptor may represent a new therapeutic target to reduce cardiac hypertrophy and hypertrophy-induced heart failure. If the safety and efficacy of a 5-HT2B receptor antagonist to treat cardiac hypertrophy or hypertrophy-induced heart failure can be confirmed in larger animal studies, application of this kind of therapy to human study may be warranted.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingThis work was supported, in part, by the National Science Council (Taipei, Taiwan) and Shin Kong Wu Ho-Su Memorial Hospital (Taipei, Taiwan).DisclosuresNone.FootnotesCorrespondence to Dr Kou-Gi Shyu, Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen-Chang RD, Taipei 111, Taiwan. E-mail [email protected] References 1 Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006; 355: 251–259.CrossrefMedlineGoogle Scholar2 Chatterjee K, Massie B. 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