Role of Leptin Signaling in the Pathogenesis of Angiotensin II–Mediated Atrial Fibrosis and Fibrillation

Abstract

The online-only Data Supplement is available at http://circep.ahajournals.org/lookup/suppl/doi:10.1161/CIRCEP.111.000104/-/DC1. Correspondence to Naohiko Takahashi, MD, PhD, Department of Laboratory Examination and Diagnostics, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail takanao@oita-u.ac.jp Background-We examined the hypothesis that leptin signaling contributes to the atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin II (AngII). Methods and Results-Eight-week-old male CL57/B6 (CNT) and leptin-deficient ob/ob mice (Ob) were subcutaneously infused with AngII (2.0 mg/kg per day). Two weeks later, transesophageal burst pacing and an electrophysiological study using isolated perfused hearts were performed. Left-atrial tissues were collected to determine interstitial fibrosis by Masson trichrome staining, and the expressions of mRNAs related to inflammatory profibrotic signals were assessed. Left-atrial fibroblasts were isolated from adult Sprague-Dawley and Zucker rats. The effects of leptin (100 ng/mL) or AngII (100 nmol/L) treatment were evaluated. In CNT-AngII mice, leptin expression in the left atrium was upregulated (P<0.01).Transesophageal burst pacing induced atrial fibrillation in 88% (7/8) of CNT-AngII mice, but not in Ob-AngII mice (0/8; P<0.01). In isolated perfused hearts, atrial fibrillation was induced only in CNT-AngII mice (4/6; 67%). Interatrial conduction time was prolonged in CNT-AngII mice (P<0.01), but not in Ob-AngII mice. The upregulation of collagen 1, collagen 3, transforming growth factor-β1, α-smooth muscle actin, MCP-1, F4/80, and RANTES mRNA, which was seen in CNT-AngII mice, was attenuated in Ob-AngII mice. In cultured Sprague-Dawley rat atrial fibroblasts, AngII treatment increased leptin expression (P<0.01). Addition of leptin increased transforming growth factor-β1, α-smooth muscle actin, MCP-1, and RANTES expressions in Sprague-Dawley rat atrial fibroblasts, but not in Zucker rat atrial fibroblasts. Conclusions-Our Fukui et al Leptin and Atrial Fibrillation 403in rat atrial fibroblasts that contain a malfunctioning receptor for leptin receptor (the Zucker rat model). MethodsAll experimental procedures were conducted in accordance with the guidelines of the Physiological Society of Oita University, Japan, for the care and use of laboratory animals, following the guidelines established by the US National Institutes of Health. For detailed Methods, see the online-only Data Supplement. Results Hemodynamic CharacteristicsSystolic blood pressure and heart rate measurements during the experimental period are shown in Figure I in the onlineonly Data Supplement. Before AngII infusion, no significant differences in these 2 parameters were observed between control (CNT) and Ob mice. Continuous AngII infusion caused elevation of systolic blood pressure and heart rate in both CNT-AngII and Ob-AngII mice (both P<0.01). We observed no significant differences in these 2 parameters between CNTAngII mice and Ob-AngII mice on days 7 and ...

The associations of leptin, adiponectin and resistin with incident atrial fibrillation in women

“…One study looking at the role of leptin in AF pathogenesis in mice, demonstrated that leptin-deficient knockout mice did not develop atrial interstitial fibrosis and subsequent AF inducibility in response to infusions of angiotensin-II compared with controls 32. These findings suggested that leptin could play a role in the pathogenesis of atrial fibrosis seen in certain patients with AF.…”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…In vivo studies examining the effects of cell-specific modulation of leptin signaling may contribute to our understanding of the role of endogenous leptin in obesity-associated cardiac remodeling. In addition to its effects on cardiomyocytes, leptin modulates fibroblast phenotype, activating a fibrogenic program (109). Whether fibroblast-specific effects of leptin mediate myocardial fibrosis in obesity has not been rigorously tested.…”

Splenectomy exacerbates atrial inflammatory fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats: Possible role of spleen-derived interleukin-10

“…10, 11 Atrial inflammatory profibrotic signals induce interstitial atrial fibrosis, which plays a critical role in AF pathogenesis. [12][13][14] For instance, hypertension-characterized by pressure overload-stimulates inflammatory profibrotic signals, leading to enhanced vulnerability to AF; [15][16][17][18][19][20][21] indeed, hypertension is a major risk factor for AF. 22 However, the role of the spleen and IL-10 in inflammatory atrial fibrosis has not been investigated.…”