title: PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction.
abstract: Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.|Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Walter E
authors: WE
authors: Knight
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.|Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Si
authors: S
authors: Chen
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Yishuai
authors: Y
authors: Zhang
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Masayoshi
authors: M
authors: Oikawa
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.|Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China 201203.
authors: Meiping
authors: M
authors: Wu
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Qian
authors: Q
authors: Zhou
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Clint L
authors: CL
authors: Miller
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Yujun
authors: Y
authors: Cai
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Deanne M
authors: DM
authors: Mickelsen
authors: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195.
authors: Christine
authors: C
authors: Moravec
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Eric M
authors: EM
authors: Small
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
authors: Junichi
authors: J
authors: Abe
authors: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641; Chen_Yan@URMC.Rochester.edu.
authors: Chen
authors: C
authors: Yan
keywords: cardiac remodeling; cyclic nucleotide; heart failure; phosphodiesterase