Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

Prisco, Sasha Z.; Thenappan, Thenappan; Prins, Kurt W.

doi:10.1016/j.jacbts.2020.07.011

Cited by 54 publications

(51 citation statements)

References 173 publications

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“…EC dysfunction is associated with progression of PH, especially in the generation of plexiform vascular lesions [ 33 ]. Moreover, cardiomyocyte hypoxic damage, apoptosis and cardiac inflammation and fibrosis occurs because of the dysfunction of ECs, since they are directly implicated in providing proper oxygen supply to cardiac cells [ 23 , 52 ]. Interestingly, PH patients also have RV capillary rarefaction, especially in the presence of underlying autoimmune disorders, such as systemic sclerosis [ 53 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

“…The endothelial dysfunction seen in PH involves lower nitric oxide (NO) production by the reduced expression and activation of endothelial NO synthase (eNOS) [ 23 ]. Gene knockdown of ROCK or its inhibition can upregulate eNOS expression in ECs by controlling the degradation of NOS3 mRNA [ 23 , 32 , 52 ]. Moreover, the inhibition of ROCK also increases eNOS phosphorylation by Akt, enhancing its catalytic activity, presumably by reducing the activation of phosphatase and tensin homologue (PTEN) [ 23 , 48 , 54 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

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ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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Pulmonary hypertension (PH) is a cardiovascular disease caused by extensive vascular remodeling in the lungs, which ultimately leads to death in consequence of right ventricle (RV) failure. While current drugs for PH therapy address the sustained vasoconstriction, no agent effectively targets vascular cell proliferation and tissue inflammation. Rho-associated protein kinases (ROCKs) emerged in the last few decades as promising targets for PH therapy, since ROCK inhibitors demonstrated significant anti-remodeling and anti-inflammatory effects. In this review, current aspects of ROCK inhibition therapy are discussed in relation to the treatment of PH and RV dysfunction, from cell biology to preclinical and clinical studies.

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Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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“…Some drugs that are under development or may be repurposed for PAH treatment have been summarized in Table 3 . Also, clinical trials targeting RV dysfunction in PAH has been extensively review by Prisco et al ( 100 ).…”

Section: Metabolic Basis Of Pahmentioning

confidence: 99%

Glutaminolysis: A Driver of Vascular and Cardiac Remodeling in Pulmonary Arterial Hypertension

Mprah

Adzika

Gyasi

et al. 2021

Front. Cardiovasc. Med.

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Pulmonary arterial hypertension (PAH) is a decimating ailment described by chronic precapillary pulmonary hypertension, an elevated mean pulmonary arterial pressure with a normal pulmonary capillary wedge pressure, and a raised pulmonary vascular resistance resulting in increased right ventricular afterload culminating in heart failure and death. Current PAH treatments regulate the vasodilatory/vasoconstrictory balance of pulmonary vessels. However, these treatment options are unable to stop the progression of, or reverse, an already established disease. Recent studies have advanced a metabolic dysregulation, featuring increased glutamine metabolism, as a mechanism driving PAH progression. Metabolic dysregulation in PAH leads to increased glutaminolysis to produce substrate to meet the high-energy requirement by hyperproliferative and apoptosis-resistant pulmonary vascular cells. This article explores the role of glutamate metabolism in PAH and how it could be targeted as an anti-remodeling therapeutic strategy.

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“…At the physiological level, PAH is characterized by chronic vasoconstriction and progressive PA wall thickening, mainly due to unbridled proliferation and apoptosis evasion of PA smooth muscle cells (PASMCs) [2,3]. As the obliterative vascular remodeling progresses, increasing pulmonary vascular resistance occurs, leading to right ventricular dysfunction and premature death [4]. Although significant strides have been made in the treatment of PAH, approved drugs that primarily address the vasoconstrictive phenotype of the disease only offer a limited benefit in terms of morbidity and mortality [5], warranting the need to develop new therapeutic strategies mainly devoted to combat the pulmonary vascular remodeling process.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

Grobs

Awada

Lemay

et al. 2021

IJMS

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Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.

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Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

Cited by 54 publications

References 173 publications

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Glutaminolysis: A Driver of Vascular and Cardiac Remodeling in Pulmonary Arterial Hypertension

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

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