Upregulation of Phosphodiesterase 1A1 Expression Is Associated With the Development of Nitrate Tolerance

Kim, Dong-Soo; Rybalkin, Sergei D.; Pi, Xinchun; Wang, Yining; Zhang, Changxi; Münzel, Thomas; Beavo, Joseph A.; Berk, Bradford C.; Yan, Chen

doi:10.1161/hc4401.098432

Cited by 182 publications

(175 citation statements)

References 27 publications

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“…At present, it is reasonable to assume that an alternate PDE isoform fulfills this capacity. Possible candidates include PDE1 (regulates ANP-mediated dilatation in porcine aorta and has been linked to nitrate tolerance [33]), PDE2 (plays a key role in regulating cGMP production in the central nervous system [34], heart [28], and adrenal cortex [35]), and PDE3 (found in the heart, vascular smooth muscle, and platelets, and may link cGMP and cAMP pathways [36]). Whatever the case may be, this differential activity of PDE5 inhibitors on the vasoactive properties of ANP gives rise to the possibility of exerting pulmonary-specific dilation by combining a PDE5 inhibitor and a natriuretic peptide ''enhancer'' (i.e., exogenous natriuretic peptide or drug increasing endogenous natriuretic peptide levels) and exploiting the synergistic activity of these two pathways, which is absent in the systemic vasculature.…”

Section: Discussionmentioning

confidence: 99%

Synergy between Natriuretic Peptides and Phosphodiesterase 5 Inhibitors Ameliorates Pulmonary Arterial Hypertension

Baliga¹,

Zhao²,

Madhani³

et al. 2008

Am J Respir Crit Care Med

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Rationale: Phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension. The mechanism(s) underlying this specificity remains unclear, but studies in genetically modified animals suggest it might be dependent on natriuretic peptide bioactivity. Objectives: We explored the interaction between PDE5 inhibitors and the natriuretic peptide system to elucidate the (patho)physiological relationship between these two cyclic GMP (cGMP)-regulating systems and potential of a combination therapy exploiting these cooperative pathways. Methods: Pharmacological evaluation of vascular reactivity was conducted in rat isolated conduit and resistance vessels from the pulmonary and systemic circulation in vitro, and in anesthetized mice in vivo. Parallel studies were undertaken in an animal model of hypoxia-induced pulmonary hypertension (PH). Measurements and Main Results: Sildenafil augments vasodilatation to nitric oxide (NO) in pulmonary and systemic conduit and resistance arteries, whereas identical vasorelaxant responses to atrial natriuretic peptide (ANP) are enhanced only in pulmonary vessels. This differential activity is mirrored in vivo where sildenafil increases the hypotensive actions of ANP in the pulmonary, but not systemic, vasculature. In hypoxia-induced PH, combination of sildenafil plus the neutral endopeptidase (NEP) inhibitor ecadotril (which increases endogenous natriuretic peptide levels) acts synergistically, in a cGMP-dependent manner, to reduce many indices of disease severity without significantly affecting systemic blood pressure.Conclusions: These data demonstrate that PDE5 is a key regulator of cGMP-mediated vasodilation by ANP in the pulmonary, but not systemic, vasculature, thereby explaining the pulmonary selectivity of PDE5 inhibitors. Exploitation of this mechanism (i.e., PDE5 and neutral endopeptidase inhibition) represents a novel, orally active combination therapy for pulmonary arterial hypertension.Keywords: guanylyl cyclase; cyclic GMP; nitric oxide; natriuretic peptides; neutral endopeptidase Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary arterial blood pressure, vascular remodeling of the pulmonary small arteries, right ventricular hypertrophy, and ultimately right ventricular failure (1, 2). Whether idiopathic PAH, familial PAH, or PAH associated with other diseases (e.g., congenital heart disease, HIV infection), the disease leads to premature death, in large part due to the paucity of satisfactory treatments, particularly vasodilators that selectively oppose the excessive vasoconstriction observed in the pulmonary vasculature, and agents able to reverse vascular wall remodeling. This therapeutic insufficiency is also a consequence of uncertainty regarding disease etiology. Current treatment options include prostacyclin analogs (3, 4) endothelin receptor antagonists (5, 6), and phosphodiesterase 5 (PDE5) inhibitors (i.e., sildenafil) (7), but despite these advances, 2-year mort...

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Section: Discussionmentioning

confidence: 99%

Synergy between Natriuretic Peptides and Phosphodiesterase 5 Inhibitors Ameliorates Pulmonary Arterial Hypertension

Baliga¹,

Zhao²,

Madhani³

et al. 2008

Am J Respir Crit Care Med

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“…The rat Ang II hypertension model was induced in Sprague-Dawley rats by infusing Ang II (0.7 mg͞kg per day) for 7 days via s.c. osmotic minipumps (model 2001; Alzet) as described (13). Control rats were infused with vehicle.…”

Section: Methodsmentioning

confidence: 99%

A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis

Ding

Abe

Heng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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113

124

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cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression. Angiotensin II (Ang II) and the ␤-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II-and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent PDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. PDE3A down-regulation activated cAMP͞PKA signaling, leading to ICER up-regulation via PKAdependent stabilization of ICER. With respect to Ang II, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang II type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.angiotension II ͉ ␤-andrenergic receptor ͉ PKC ͉ heart failure C ardiac remodeling including dysregulated myocyte apoptosis contributes to the development and progression of myocardial remodeling and the transition from cardiac hypertrophy to chronic heart failure (1-3). Stimulation of the renin-angiotensin and ␤-adrenergic receptor (␤-AR) systems are broadly involved in contraction, growth control, and cell death (3, 4). Both systems are subject to counterregulatory balances under normal physiological circumstances, which are overridden by chronic activation in heart failure. For example, chronic exposure to angiotensin II (Ang II) and ISO promote cardiac dysfunction resulting from cardiac remodeling including hypertrophy and apoptosis (4-7). Many clinical trials have indicated that angiotensinconverting enzyme inhibitors and ␤-AR blockers significantly improve the survival rates of heart failure patients by decreasing cardiac remodeling (8). However, the exact mechanisms of myocyte apoptosis, especially those mediated by angiotensin II, remain unclear.cAMP signaling plays important roles in both physiologic and pathologic regulation of cardiac performance (9). cAMP is one of the most well characterized signaling molecules in ␤-AR signaling, but its contribution to Ang II signaling in cardiomyocytes is not fully understood. Clinical and experimental studies indicate that acute stimulation of ␤-AR...

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“…PDE1A1 is selectively upregulated by chronic exposure to nitrates (192) and may contribute to nitrate tolerance. PDE1C is upregulated in proliferating human VSMCs and atherosclerotic lesions, and a PDE1 inhibitor suppresses proliferation (312).…”

Section: Calmodulin-binding Phosphodiesterases (Pde1)mentioning

confidence: 99%

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Francis

Blount

Corbin

2011

Physiological Reviews

567

546

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The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

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Upregulation of Phosphodiesterase 1A1 Expression Is Associated With the Development of Nitrate Tolerance

Cited by 182 publications

References 27 publications

Synergy between Natriuretic Peptides and Phosphodiesterase 5 Inhibitors Ameliorates Pulmonary Arterial Hypertension

Synergy between Natriuretic Peptides and Phosphodiesterase 5 Inhibitors Ameliorates Pulmonary Arterial Hypertension

A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

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