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PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction
Walter E Knight1,2, Si Chen1,2, Yishuai Zhang1
1Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14641.
Insights
Cyclic nucleotide phosphodiesterase 1C (PDE1C) plays a key role in pathological cardiac remodeling and dysfunction. Inhibiting PDE1C in failing hearts may offer significant therapeutic benefits for heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Enzyme Function
Background:
- Cyclic nucleotide phosphodiesterase 1C (PDE1C) is a major phosphodiesterase in the human heart, but its specific role in cardiac function is not well understood.
- Cardiac remodeling and dysfunction are significant contributors to heart failure.
- Understanding the molecular mechanisms underlying cardiac remodeling is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the expression, regulation, function, and mechanisms of PDE1C in the context of cardiac remodeling and dysfunction.
- To determine the role of PDE1C in cardiac myocyte death, hypertrophy, and fibroblast activation.
- To evaluate the therapeutic potential of targeting PDE1C in pathological cardiac conditions.
Main Methods:
- Utilized genetic (PDE1C-knockout mice) and pharmacological inhibition approaches.
- Examined PDE1C expression in mouse and human failing hearts and isolated cardiac myocytes.
- Assessed the impact of PDE1C deficiency/inhibition on cardiac myocyte apoptosis and hypertrophy.
- Investigated the effects on cardiac fibroblast activation and in vivo cardiac remodeling following transverse aortic constriction.
Main Results:
- PDE1C expression is upregulated in failing hearts and localized to cardiac myocytes.
- PDE1C deficiency or inhibition attenuated cardiac myocyte death, apoptosis (via cAMP/PKA and PI3K/AKT pathways), and hypertrophy (via PKA).
- Conditioned media from PDE1C-deficient myocytes reduced TGF-β-stimulated fibroblast activation, indicating myocyte-fibroblast crosstalk modulation.
- PDE1C knockout mice showed significantly attenuated cardiac remodeling and dysfunction in response to pressure overload.
Conclusions:
- PDE1C activation is a causative factor in pathological cardiac remodeling and dysfunction.
- Targeting PDE1C may represent a promising therapeutic strategy for treating heart failure.
- The high expression of PDE1C in the human heart underscores its potential as a drug target.
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.
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