Pulmonary Arterial Hypertension and Therapeutic Interventions

Gabra, Nader B. Ishak; Mahmoud, Omar; Ishikawa, O.; Shah, Varun; Altshul, Erica; Oron, Maly; Mina, Bushra

doi:10.1055/s-0039-1692452

Cited by 5 publications

(7 citation statements)

References 97 publications

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“…The most effective strategy to alleviate PH symptoms is to promote both cGMP and cAMP signalling enhancing vasodilation [ 196 , 198 , 199 ]. While PDE5 inhibitors have been extensively studied for clinical use to treat PH [ 198 , 200 , 201 ], PDE2 has not been comprehensively investigated and only one study demonstrated that PDE2 inhibition may ameliorate PH [ 196 ]. In this study, the authors demonstrated that PDE2 inhibition with BAY60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH.…”

Section: Role Of Pde2 In Cardiovascular Diseasementioning

confidence: 99%

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

Sadek

Cachorro

El‐Armouche

et al. 2020

IJMS

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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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Section: Role Of Pde2 In Cardiovascular Diseasementioning

confidence: 99%

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

Sadek

Cachorro

El‐Armouche

et al. 2020

IJMS

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show abstract

“…The most effective strategy to alleviate PH symptoms is to promote both cGMP and cAMP signalling enhancing vasodilation [172,174,175]. While PDE5 inhibitors have been extensively studied for clinical use to treat PH [174,176,177], PDE2 has not been comprehensively investigated and only one study demonstrated that PDE2 inhibition may ameliorate PH [172].…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

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

Sadek¹,

Cachorro²,

Kämmerer³

et al. 2020

Preprint

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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. 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 signalling with cardioprotective cGMP signalling. 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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“…Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic condition that comprises heterogeneous disorders, leads to right-heart failure if untreated, and carries substantial morbidity and mortality (1)(2)(3)(4). It is defined as a mean pulmonary arterial pressure exceeding 20 mmHg at rest as assessed by right-heart catheterization (5).…”

Section: Introductionmentioning

confidence: 99%

Schistosome-Associated Pulmonary Arterial Hypertension: A Review Emphasizing Pathogenesis

Ferrari

Albricker

Gonçalves

et al. 2021

Front. Cardiovasc. Med.

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Schistosomiasis, especially due to Schistosoma mansoni, is a well-recognized cause of pulmonary arterial hypertension (PAH). The high prevalence of this helminthiasis makes schistosome-related PAH (Sch-PAH) one of the most common causes of this disorder worldwide. The pathogenic mechanisms underlying Sch-PAH remain largely unknown. Available evidence suggests that schistosome eggs reach the lung via portocaval shunts formed as a consequence of portal hypertension due to hepatosplenic schistosomiasis. Once deposited into the lungs, the eggs elicit an immune response resulting in periovular granuloma formation. Immune mediators drive transforming growth factor-β (TGF-β) release, which gives rise to pulmonary vascular inflammation with subsequent remodeling and development of angiomatoid and plexiform lesions. These mechanisms elicited by the eggs seem to become autonomous and the vascular lesions progress independently of the antigen. Portopulmonary hypertension, which pathogenesis is still uncertain, may also play a role in the genesis of Sch-PAH. Recently, there have been substantial advances in the diagnosis and treatment of PAH, but it remains a difficult condition to recognize and manage, and patients still die prematurely from right-heart failure. Echocardiography is used for screening, and the formal diagnosis requires right-heart catheterization. The experience in treating Sch-PAH is largely limited to the phosphodiesterase type 5 inhibitors, with evidence suggesting that these vasodilators improve symptoms and may also improve survival. Considering the great deal of uncertainty about Sch-PAH pathogenesis, course, and treatment, the aim of this review is to summarize current knowledge on this condition emphasizing its pathogenesis.

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Pulmonary Arterial Hypertension and Therapeutic Interventions

Cited by 5 publications

References 97 publications

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

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

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

Schistosome-Associated Pulmonary Arterial Hypertension: A Review Emphasizing Pathogenesis

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