Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction

Ma, Dan; Fu, Lu; Shen, Jing-xia; Zhou, Ping; Yu-fei, Gao; Xie, Ruiqin; Li, Yuanshi; Han, Ying; Wang, Yumei; Wang, Fei

doi:10.1016/j.ejphar.2008.11.002

Cited by 9 publications

(11 citation statements)

References 24 publications

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“…The current study directly tests the hypothesis that chronic over-expression of ICER from excessive β-adrenergic signaling 28,29 may repress miR-1 expression leading to the well documented electrical remodeling. First, by taking advantage of a knockout model of Dicer1 in the heart, we demonstrated the direct regulation of cardiac excitability by miRs .…”

Section: Discussionmentioning

confidence: 91%

“…Under chronic pathological conditions, excessive β-adrenergic signaling drives a progressive increase in ICER expression that may contribute to inhibition of CREB-dependent gene expression and β-adrenergic desensitization. 28,29 Recent studies have documented the beneficial effects of preserving β-adrenergic sensitivity after an MI 30,31 and knockout of CREM was shown to be protective under chronic β-adrenergic signaling. 32 In addition, cardiac-specific knockout of CREB led to electrical remodeling in cardiomyocytes similar to that seen post MI with a loss of I to and prolonged action potential durations (APDs).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, we hypothesize that under pathological conditions, chronic over-expression of ICER from excessive β-adrenergic signaling 28,29 may repress miR-1 expression leading to the well documented electrical remodeling. To test the hypothesis, we first examined the roles of miRs in the regulation of cardiac excitability by taking advantage of a knockout model of Dicer1 and cardiac delivery of Cre Recombinase.…”

Section: Introductionmentioning

confidence: 99%

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Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling

Timofeyev

Kim

et al. 2015

Circ: Arrhythmia and Electrophysiology

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Background Loss of transient outward K+ current (Ito) is well documented in cardiac hypertrophy and failure both in animal models and humans. Electrical remodeling contributes to prolonged action potential duration (APD) and increased incidence of arrhythmias. Furthermore, there is a growing body of evidence linking microRNA (miR) dysregulation to the progression of both conditions. In this study, we examined the mechanistic basis underlying miR dysregulation in electrical remodeling and revealed a novel interaction with the adrenergic signaling pathway. Methods and Results We first employed a tissue-specific knockout model of Dicer1 in cardiomyocytes to reveal the overall regulatory effect of miRs on the ionic currents and action potentials. We then validated the inducible cAMP early repressor (ICER) as a target of miR-1 and took advantage of a clinically relevant model of post myocardial infarction (MI) and miR delivery to probe the mechanistic basis of miR dysregulation in electrical remodeling. These experiments revealed the role of ICER as a repressor of miR-1 and Ito, leading to prolonged APD post MI. In addition, delivery of miR-1 and miR-133a suppressed ICER expression and prevented both electrical remodeling and hypertrophy. Conclusions Taken together, our results illuminate the mechanistic links between miRs, adrenergic signaling, and electrical remodeling. They also serve as a proof-of-concept for the therapeutic potential of miR delivery post MI.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling

Timofeyev

Kim

et al. 2015

Circ: Arrhythmia and Electrophysiology

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“…Interestingly, PDE3A downregulation has been found in human failing hearts as well as in hearts from animals with cardiac hypertrophy and/or dysfunction [45,48–51]. Restoring cardiac function in experimental models of heart failure, including treatment with angiotensin receptor antagonists or overexpression of constitutively active mitogen-activated protein/extracellular signal-regulated protein kinase (CA-MEK5α), prevented PDE3A downregulation and ICER induction [50]. These results strongly suggest that chronically blocking PDE3A function promotes cardiomyocyte apoptosis and accelerates development of cardiac dysfunction.…”

Section: Pde3mentioning

confidence: 99%

Therapeutic Potential of Pde Modulation in Treating Heart Disease

Knight

Yan

2013

Future Med. Chem.

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Altered cyclic nucleotide-mediated signaling plays a critical role in the development of cardiovascular pathology. By degrading cAMP/cGMP, the action of cyclic nucleotide PDEs is essential for controlling cyclic nucleotide-mediated signaling intensity, duration, and specificity. Altered expression, localization and action of PDEs have all been implicated in causing changes in cyclic nucleotide signaling in cardiovascular disease. Accordingly, pharmacological inhibition of PDEs has gained interest as a treatment strategy and as an area of drug development. While targeting of certain PDEs has the potential to ameliorate cardiovascular disease, inhibition of others might actually worsen it. This review will highlight recent research on the physiopathological role of cyclic nucleotide signaling, especially with regard to PDEs. While the physiological roles and biochemical properties of cardiovascular PDEs will be summarized, the primary emphasis will be pathological. Research into the potential benefits and hazards of PDE inhibition will also be discussed.

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“…Downregulation of PDE3A expression and upregulation of ICER are indeed found in tissue from various animal models of heart disease and from humans hearts with ischemic and dilated cardiomyopathies [77–80]. Interestingly, when cardiac function is improved by overexpression of a constitutively active form of mitogen-activated protein/extracellular signal-regulated protein kinase (CA-MEK5α) or using the angiotensin receptor antagonist valsartan, PDE3A and ICER levels are restored [79,81]. Valsartan treatment also reduces cardiomyocyte apoptosis and improves hemodynamics in mice after myocardial infarction [81].…”

Section: Regulation and Function Of Pdes In Pathological Cardiac Remomentioning

confidence: 99%

Cardiac Cyclic Nucleotide Phosphodiesterases: Function, Regulation, and Therapeutic Prospects

Knight

Yan

2012

Horm Metab Res

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The second messengers cAMP and cGMP exist in multiple discrete compartments and regulate a variety of biological processes in the heart. The cyclic nucleotide phosphodiesterases, by catalyzing the hydrolysis of cAMP and cGMP, play crucial roles in controlling the amplitude, duration, and compartmentalization of cyclic nucleotide signaling. Over 60 phosphodiesterase isoforms, grouped into 11 families, have been discovered to date. In the heart, both cAMP- and cGMP-hydrolyzing phosphodiesterases play important roles in physiology and pathology. At least 7 of the 11 phosphodiesterase family members appear to be expressed in the myocardium, and evidence supports phosphodiesterase involvement in regulation of many processes important for normal cardiac function including pacemaking and contractility, as well as many pathological processes including remodeling and myocyte apoptosis. Pharmacological inhibitors for a number of phosphodiesterase families have also been used clinically or preclinically to treat several types of cardiovascular disease. In addition, phosphodiesterase inhibitors are also being considered for treatment of many forms of disease outside the cardiovascular system, raising the possibility of cardiovascular side effects of such agents. This review will discuss the roles of phosphodiesterases in the heart, in terms of expression patterns, regulation, and involvement in physiological and pathological functions. Additionally, the cardiac effects of various phosphodiesterase inhibitors, both potentially beneficial and detrimental, will be discussed.

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Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction

Cited by 9 publications

References 24 publications

Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling

Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling

Therapeutic Potential of Pde Modulation in Treating Heart Disease

Cardiac Cyclic Nucleotide Phosphodiesterases: Function, Regulation, and Therapeutic Prospects

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