Abstract 17219: Fibroblast-specific Beta-adrenergic Receptor Signaling Regulates Cardiac Hypertrophy in Mice

• Published in: Circulation (New York, N.Y.) Vol. 134; no. Suppl_1 Suppl 1; p. A17219
• Main Authors: Tonegawa, Kota, Tanaka, Shota, Takahashi, Misato, Fuchigami, Shota, Obana, Masanori, Maeda, Makiko, Sakata, Yasushi, Fujio, Yasushi, Nakayama, Hiroyuki
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 11.11.2016
• ISSN: 0009-7322; 1524-4539

Backgroundβ adrenergic signaling plays a central role in development of human heart failure. In mice, chronic β adrenergic receptor (β-AR) stimulation elicits cardiac hypertrophy. Recently, it is reported that cardiac fibroblasts express β-AR, however, functional role of β-AR signaling in cardiac fibroblasts in development of cardiac hypertrophy remains elusive.ObjectiveTo elucidate the role of fibroblast-specific βAR signaling in cardiac hypertrophy.Methods and Resultsβ2AR null mice (β2ARKO) and wild-type (WT) were employed to assess hypertrophic response to chronic β-AR stimulation by continuous infusion of isoproterenol (ISO, 50mg/kg/day) using Alzet mini-pump. As a result, β2ARKO demonstrated less hypertrophy compared to WT. Heart weight normalized to body weight ratio (HW/BW) was significantly lower in β2ARKO compared to WT after ISO stimulation (5.1±0.4 mg/kg, n=9 vs 5.8±0.2 mg/kg, n=7; p<.05), and the expression of ANF was significantly suppressed in β2ARKO compared to WT (0.25±0.06 vs 1.00±0.43, in fold increases, n=5 each; p<.05), suggesting β2AR activation in heart induces pro-hypertrophic effect in mice. Since β2AR signaling is known as protective in cardiomyocytes, we focused on β2AR signaling in cardiac fibroblasts. To determine whether β2AR signaling in fibroblast affect cardiac hypertrophy induced by ISO stimulation, we generated fibroblast-specific transgenic mice (TG) with catalytic subunit of protein kinase A (PKAcα) using Cre-loxP system. Two responder TG lines were obtained and crossbred with periostin-Cre TG to achieve fibroblast-specific PKA activation. Fibroblast-specific PKAcα overexpression mediated increased HW/BW ratio (5.4±0.3 mg/kg vs 4.5±0.1 mg/kg, n=5 each; p<.05) associated with increased size of cardiomyocytes at 12 weeks of age, suggesting fibroblast-specific activation of PKA mediates cardiac hypertrophy in mice.Conclusionβ2AR deletion attenuated ISO-induced cardiac hypertrophy in mice and fibroblast-specific activation of PKA induced cardiac hypertrophy, suggesting β2AR signaling in fibroblast plays a central role in ISO-induced cardiac hypertrophy. Thus, β2AR signaling in cardiac fibroblast could be a promising target to develop a novel therapeutic tool for heart failure.