Abstract
Phosphodiesterase 1C (PDE1C) is expressed in mammalian heart and regulates cardiac functions by controlling levels of second messenger cyclic AMP and cyclic GMP (cAMP and cGMP, respectively). However, molecular mechanisms of cardiac Pde1c regulation are currently unknown. In this study, we demonstrate that treatment of wild type mice and H9c2 myoblasts with Wy-14,643, a potent ligand of nuclear receptor peroxisome-proliferator activated receptor alpha (PPARα), leads to elevated cardiac Pde1C mRNA and cardiac PDE1C protein, which correlate with reduced levels of cAMP. Furthermore, using mice lacking either Pparα or cardiomyocyte-specific Med1, the major subunit of Mediator complex, we show that Wy-14,643-mediated Pde1C induction fails to occur in the absence of Pparα and Med1 in the heart. Finally, using chromatin immunoprecipitation assays we demonstrate that PPARα binds to the upstream Pde1C promoter sequence on two sites, one of which is a palindrome sequence (agcTAGGttatcttaacctagc) that shows a robust binding. Based on these observations, we conclude that cardiac Pde1C is a direct transcriptional target of PPARα and that Med1 may be required for the PPARα mediated transcriptional activation of cardiac Pde1C.
Highlights
Heart failure is the result of a multitude of malfunctions associated with decreased cardiac output, dilatation, or hypertrophy of the myocardium, loss of contractility, and impaired mitochondrial function
To test whether cardiac genes respond to a PPARα agonist in vitro in isolated cells and whether PPARα binds to the Pde1C promoter, we used H9c2 rat cardiomyocytes in these assays
We recently showed that mice lacking cardiomyocyte-specific Mediator subunit 1 (Med1) expression have reduced Pparα expression as well as reduced expressions of important genes involved in PPARα-regulated cardiac energy metabolism, cardiac muscle contraction, and calcium signaling, including Pde1c [14]
Summary
Heart failure is the result of a multitude of malfunctions associated with decreased cardiac output, dilatation, or hypertrophy of the myocardium, loss of contractility, and impaired mitochondrial function. Phosphodiesterases (PDEs) play an important role in regulating cardiac contractile function owing to their ability to modulate levels of the critical second messengers cyclic AMP and cyclic GMP (cAMP and cGMP, respectively) [1]. These cyclic nucleotides control a number of cardiac functions including acute effects on cardiomyocyte contraction and mitochondrial function as well as chronic effects on growth and metabolism [2,3]. Despite multiple evidence of the important role of PDE1C in cardiac functions, the molecular mechanisms that regulate its level and activity remain to be explored
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