PDE2 at the crossway between cAMP and cGMP signalling in the heart

Weber, Silvio; Zeller, Miriam; Guan, Kaomei; Wunder, Frank; Wagner, Michael; El‐Armouche, Ali

doi:10.1016/j.cellsig.2017.06.020

Cited by 48 publications

(37 citation statements)

References 120 publications

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“…Microvascular patency is primarily regulated by endothelium-dependent relaxation. 46 Interestingly, the content of endothelial nitric oxide synthase (eNOS) was decreased to a significantly greater extent by IR injury but increased to normal levels via Ripk3 deletion or melatonin treatment, as gauged by Western blots (Figure 2C-E). However, regaining of Ripk3 antagonized the promoting effects of melatonin in terms of eNOS production under IR injury.…”

Section: Melatonin Sustains Microvascular Patency Via Blocking Ripk3mentioning

confidence: 94%

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

Zhou

Zhu

et al. 2018

Journal of Pineal Research

193

168

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The molecular features of necroptosis in cardiac ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition pore) opening. Interestingly, melatonin supplementation suppressed mPTP opening and interrupted endothelial necroptosis via blocking the Ripk3-PGAM5-CypD signal pathways. Taken together, our studies identified the Ripk3-PGAM5-CypD-mPTP axis as a new pathway responsible for reperfusion-mediated microvascular damage via initiating endothelial necroptosis. In contrast, melatonin treatment inhibited the Ripk3-PGAM5-CypD-mPTP cascade and thus reduced cellular necroptosis, conferring a protective advantage to the endothelial system in IR stress. These findings establish a new paradigm in microvascular IR injury and update the concept for cell death management handled by melatonin under the burden of reperfusion attack.

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Section: Melatonin Sustains Microvascular Patency Via Blocking Ripk3mentioning

confidence: 94%

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

Zhou

Zhu

et al. 2018

Journal of Pineal Research

193

168

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“…The puzzling observation that inhibition of AC or PKA leads to stimulation of insulin secretion may be due to a cross talk between cAMP and cGMP as described for other organs (42,43), especially activation of a cGMPspecific PDE by PKA (44,45). Inhibition of PKA would thus increase cGMP concentration, leading to protein kinase G (PKG)-dependent closure of K ATP channels (46).…”

Section: Ola Acts Via a Camp/pka-dependent Pathwaymentioning

confidence: 99%

TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic β-Cells via a PKA-Dependent Pathway

et al. 2018

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The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in b-cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine b-cell function by TGR5 activation. Both a G as inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted stimulus-secretion coupling (SSC). OLA reduced K ATP current and elevated current through Ca 2+ channels. Accordingly, in mouse and human b-cells, TGR5 ligands increased the cytosolic Ca 2+ concentration by stimulating Ca 2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counterregulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide 3-kinase did not prevent stimulating effects of OLA. Involvement of exchange protein directly activated by cAMP 2 (Epac2) or farnesoid X receptor (FXR2) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local glucagon-like peptide 1 (GLP-1) secretion from a-cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in b-cells stimulates insulin secretion via an AC/cAMP/PKA-dependent pathway, which is supposed to interfere with SSC by affecting K ATP and Ca 2+ currents and thus membrane potential.In recent years, it became evident that the membrane protein Takeda-G-protein-receptor-5 (TGR5), also known as GPBA, MBAR, or Gpbar1, plays an important role in energy and glucose metabolism (1,2). TGR5 is present in several tissues and cell types including heart, spleen, intestine, macrophages, and pancreas (3,4). The receptor is involved in physiological processes such as inflammation, gallbladder filling, gastrointestinal motility, and thermogenesis (1,5-7). TGR5 stimulates secretion of glucagon-like peptide 1 (GLP-1) from intestinal L cells and thus regulates glucose metabolism (8-10). TGR5 activation leads to energy expenditure, which in turn improves glucose homeostasis (9). Noteworthy, after vertical sleeve gastrectomy, TGR5 contributes to the beneficial effects of the surgery (11).The endogenous ligands of the receptor are bile acids that potently regulate glucose homeostasis (3). For oleanolic acid (OLA), a triterpene isolated from Olea europaea that improves metabolic disorders and has antidiabetes effects (12,13), the situation is less clear. While OLA is proposed to be a TGR5 agonist in pancreatic islets by one study (4), another group excludes an increase in cAMP concentration by OLA normally observed downstream of TGR5 activation (14). In addition, direct effects of OLA on b-cells through increased acetylcholine leve...

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“…In addition to cyclic nucleotides, PDE2 has also been reputed to associate with scaffold proteins via high-throughput screening studies [ 133 ]. PDE2 was shown to interact with XAP2, a crucial component of the aryl hydrocarbon receptor (AhR) complex playing an important role in cardiomyocyte differentiation and hypertrophy [ 134 , 135 ].…”

Section: Cyclic Nucleotide Signalling and Compartmentalizationmentioning

confidence: 99%

“…Within the cardiovascular system, PDE2 is predominantly expressed in endothelial cells and in cardiac fibroblasts but is modestly expressed in cardiomyocytes under physiological conditions [ 133 , 143 , 144 ]. Prominent PDE2 expression is notable in various neuronal cell types within the central nervous system and thereby PDE2 activity in sympathetic neurons also modulates the cardiac function [ 145 , 146 , 147 , 148 ].…”

Section: Pde2 Functions In the Cardiovascular Systemmentioning

confidence: 99%

“…Despite the limited expression of PDE2 in cardiomyocytes and its modest contribution to the total cAMP hydrolytic activity (~3%) under physiological conditions, PDE2 remains a well-recognized and important modulator of cardiac function [ 131 , 133 , 154 ]. PDE2 has been shown to finely coordinate critical cAMP pools governing β-AR signalling, cardiomyocyte contractility, Ca 2+ homeostasis and mitochondrial function ( Figure 2 ) [ 122 , 154 , 155 ].…”

Section: Pde2 Functions In the Cardiovascular Systemmentioning

confidence: 99%

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Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

Sadek

Cachorro

El‐Armouche

et al. 2020

IJMS

Self Cite

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Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3′,5′-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.

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PDE2 at the crossway between cAMP and cGMP signalling in the heart

Cited by 48 publications

References 120 publications

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic β-Cells via a PKA-Dependent Pathway

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

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