Multiprotein Complex With TRPC (Transient Receptor Potential-Canonical) Channel, PDE1C (Phosphodiesterase 1C), and A2R (Adenosine A2 Receptor) Plays a Critical Role in Regulating Cardiomyocyte cAMP and Survival

Zhang, Yishuai; Knight, Walter E.; Chen, Si; Mohan, Amy; Yan, Chen

doi:10.1161/circulationaha.118.034189

Cited by 45 publications

(37 citation statements)

References 39 publications

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“…Immuno-histochemistry localizes A 2B R at mitochondria 45 and it is also expressed in vascular tissue and fibroblasts where it regulates proliferation, vascular tone, and anti-fibrotic signaling 46 . PDE1 inhibition is also antifibrotic 47 , regulates smooth muscle proliferation 48 , and as shown by Zhang et al 49 , also protects against doxorubicin-induced myocyte apoptosis in vitro and in vivo . In this study, they found PDE1 co-localizes with A 2 R in a membrane macromolecular complex overlapping t-tubules, and that both A 2A R and A 2B R blockade prevents the anti-apoptotic efficacy from PDE1 inhibition.…”

Section: Discussionmentioning

confidence: 82%

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition

et al. 2018

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Section: Discussionmentioning

confidence: 82%

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition

et al. 2018

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“…The anti-apoptotic effects of PDE1C deficiency or inhibition were mediated by the cAMP/PKA axis ( 18 ). Zhang et al ( 25 ) further demonstrated that PDE1C colocalized with adenosine A2 receptors (A 2 Rs) in cardiomyocyte membrane and T-tubules and that the anti-apoptotic effect of PDE1 inhibition is dependent on cAMP-generating A 2 Rs in cardiomyocytes, suggesting that PDE1C selectively regulates A 2 R/cAMP signaling in cardiomyocytes. Since impaired PQC resulting from PFI is sufficient to cause cardiomyocytes to die, proteasome enhancement may also contribute to the prosurvival effect of PDE1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy

Zhang

Pan

et al. 2019

Sci. Adv.

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No current treatment targets cardiac proteotoxicity or can reduce mortality of heart failure (HF) with preserved ejection fraction (HFpEF). Selective degradation of misfolded proteins by the ubiquitin-proteasome system (UPS) is vital to the cell. Proteasome impairment contributes to HF. Activation of cAMP-dependent protein kinase (PKA) or cGMP-dependent protein kinase (PKG) facilitates proteasome functioning. Phosphodiesterase 1 (PDE1) hydrolyzes both cyclic nucleotides and accounts for most PDE activities in human myocardium. We report that PDE1 inhibition (IC86430) increases myocardial 26S proteasome activities and UPS proteolytic function in mice. Mice with CryABR120G-based proteinopathy develop HFpEF and show increased myocardial PDE1A expression. PDE1 inhibition markedly attenuates HFpEF, improves mouse survival, increases PKA-mediated proteasome phosphorylation, and reduces myocardial misfolded CryAB. Therefore, PDE1 inhibition induces PKA- and PKG-mediated promotion of proteasomal degradation of misfolded proteins and treats HFpEF caused by CryABR120G, representing a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.

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“…Moreover, in tissues, PDE1C can degrade cyclic AMP, which conducts several subcellular functions that result in positive inotropic and lusitropic effects [3]. Recent studies have demonstrated that PDE1C is an important regulator of cardiac cAMP signaling and has a direct role in cardiomyocyte death/apoptosis [7,36]. Emerging studies suggest that it may be an important candidate for therapeutic targeting in heart failure [7,37].…”

Section: Discussionmentioning

confidence: 99%

Mouse Cardiac Pde1C Is a Direct Transcriptional Target of Pparα

Shete

Liu

Jia

et al. 2018

IJMS

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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.

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Multiprotein Complex With TRPC (Transient Receptor Potential-Canonical) Channel, PDE1C (Phosphodiesterase 1C), and A2R (Adenosine A2 Receptor) Plays a Critical Role in Regulating Cardiomyocyte cAMP and Survival

Cited by 45 publications

References 39 publications

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition

PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy

Mouse Cardiac Pde1C Is a Direct Transcriptional Target of Pparα

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