Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway

Mei, Lin; Zheng, Yun‐Min; Song, Tengyao; Yadav, Vishal; Joseph, Leroy C.; Truong, Lillian; Kandhi, Sharath; Barroso, Margarida; Takeshima, Hiroshi; Judson, Marc A.; Wang, Yong-Xiao

doi:10.1038/s41467-020-17314-1

Cited by 23 publications

(46 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, when PAH occurs, there are molecular markers of tumor cells on the blood vessels, which have been proved to play an important role in the pathological process of PAH [ 11 ]. More and more studies have found that various pathological manifestations of PAHS can be explained by the metabolic theory originally used for tumors, and mitochondrial abnormalities are the core of this theory [ 12 ]. PASMC also has the characteristic of enhanced glycolysis reaction of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

Chen

Jiang

Zhu

et al. 2021

BioMed Research International

View full text Add to dashboard Cite

Objective. To investigate the role of curcumin in regulating pathogenesis of pulmonary arterial smooth muscle cells (PASMCs) derived from pulmonary arterial hypertension (PAH) model. Methods. Male Sprague Dawley rats were injected with monocrotaline (MCT) to establish the PAH experimental model. The rats were divided into control group, MCT group, and curcumin group. At the end of the study, hemodynamic data were measured to determine pulmonary hypertension. Proliferation ability of PASMCs, a remodeling indicator of pulmonary artery and right ventricle, was detected. In addition, the morphology and function of mitochondria, antiglycolysis and antiproliferation pathways, and genes were also analyzed. Results. Curcumin may function by reversing MCT-mediated pulmonary vascular remodeling in rats. Curcumin effectively improved pulmonary vascular remodeling, promoted PASMC apoptosis, and protected mitochondrial function. In addition, curcumin treatment suppressed the PI3K/AKT pathway in PASMCs and regulated the expression of antiproliferative genes. Conclusion. Curcumin can improve energy metabolism and reverse the process of PAHS. However, there were side effects of curcumin in MCT-induced rats, suggesting that the dosage should be treated with caution and its toxicological mechanism should be further studied and evaluated.

show abstract

Section: Introductionmentioning

confidence: 99%

Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

Chen

Jiang

Zhu

et al. 2021

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…Herein, it was found that dasatinib could directly induce PASMCs proliferation via increasing cell viability and arresting cell cycle process. As one of the key regulators for G1/S transition in the cell cycle, cyclin D1 is up-regulated in excessively proliferative PASMCs by hypoxia, resulting in pulmonary vascular remodeling and PH ( 55 , 56 ). Notably, our results indicated that melatonin reversed the up-regulation of cyclin D1 and led to cell cycle G0/G1 phase arrest induced by dasatinib under hypoxia in primary rat PASMCs.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Attenuates Dasatinib-Aggravated Hypoxic Pulmonary Hypertension via Inhibiting Pulmonary Vascular Remodeling

Wang

Pan

Han

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Dasatinib treatment is approved as first-line therapy for chronic myeloid leukemia. However, pulmonary hypertension (PH) is a highly morbid and often fatal side-effect of dasatinib, characterized by progressive pulmonary vascular remodeling. Melatonin exerts strong antioxidant capacity against the progression of cardiovascular system diseases. The present work aimed to investigate the effect of melatonin on dasatinib-aggravated hypoxic PH and explore its possible mechanisms. Dasatinib-aggravated rat experimental model of hypoxic PH was established by utilizing dasatinib under hypoxia. The results indicated that melatonin could attenuate dasatinib-aggravated pulmonary pressure and vascular remodeling in rats under hypoxia. Additionally, melatonin attenuated the activity of XO, the content of MDA, the expression of NOX4, and elevated the activity of CAT, GPx, and SOD, the expression of SOD2, which were caused by dasatinib under hypoxia. In vitro, dasatinib led to decreased LDH activity and production of NO in human pulmonary microvascular endothelial cells (HPMECs), moreover increased generation of ROS, and expression of NOX4 both in HPMECs and primary rat pulmonary arterial smooth muscle cells (PASMCs) under hypoxia. Dasatinib up-regulated the expression of cleaved caspase-3 and the ratio of apoptotic cells in HPMECs, and also elevated the percentage of S phase and the expression of Cyclin D1 in primary PASMCs under hypoxia. Melatonin ameliorated dasatinib-aggravated oxidative damage and apoptosis in HPMECs, meanwhile reduced oxidative stress level, proliferation, and repressed the stability of HIF1-α protein in PASMCs under hypoxia. In conclusion, melatonin significantly attenuates dasatinib-aggravated hypoxic PH by inhibiting pulmonary vascular remodeling in rats. The possible mechanisms involved protecting endothelial cells and inhibiting abnormal proliferation of smooth muscle cells. Our findings may suggest that melatonin has potential clinical value as a therapeutic approach to alleviate dasatinib-aggravated hypoxic PH.

show abstract

“…Major sources of these species are mitochondria and cytoplasmic enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) [4]. For a long time, mitochondrial O 2 derivatives were considered harmful cellular chemical entities; nevertheless, there is increasing evidence showing that ROS are not only toxic oxidants 2 of 21 but serve as signaling molecules implicated in several processes, such as cytosolic Ca 2+ signaling [5][6][7][8][9], gene transcription [10] and protein synthesis [11]. The impairment of mitochondria function (mitochondrial dysfunction) affects almost any functional tissue in the body, e.g., pancreas, skeletal, cardiac and smooth muscle, nerves, kidney, and lungs among others [12].…”

Section: Introductionmentioning

confidence: 99%

“…The impairment of mitochondria function (mitochondrial dysfunction) affects almost any functional tissue in the body, e.g., pancreas, skeletal, cardiac and smooth muscle, nerves, kidney, and lungs among others [12]. Mitochondrial dysfunction due to alterations in ROS production and mitochondrial DNA (mitDNA) damage underlies critical pathophysiological mechanisms in numerous diseases such as diabetes [13,14], fibromyalgia [15], chronic heart failure [16], Alzheimer's disease [17], chronic kidney disease [18], atherosclerosis [19], and pulmonary hypertension (PH) [5,20]. In this regard, the role of ROS has been extensively investigated in vascular biology.…”

Section: Introductionmentioning

confidence: 99%

Important Functions and Molecular Mechanisms of Mitochondrial Redox Signaling in Pulmonary Hypertension

et al. 2022

Self Cite

View full text Add to dashboard Cite

Mitochondria are important organelles that act as a primary site to produce reactive oxygen species (ROS). Additionally, mitochondria play a pivotal role in the regulation of Ca2+ signaling, fatty acid oxidation, and ketone synthesis. Dysfunction of these signaling molecules leads to the development of pulmonary hypertension (PH), atherosclerosis, and other vascular diseases. Features of PH include vasoconstriction and pulmonary artery (PA) remodeling, which can result from abnormal proliferation, apoptosis, and migration of PA smooth muscle cells (PASMCs). These responses are mediated by increased Rieske iron–sulfur protein (RISP)-dependent mitochondrial ROS production and increased mitochondrial Ca2+ levels. Mitochondrial ROS and Ca2+ can both synergistically activate nuclear factor κB (NF-κB) to trigger inflammatory responses leading to PH, right ventricular failure, and death. Evidence suggests that increased mitochondrial ROS and Ca2+ signaling leads to abnormal synthesis of ketones, which play a critical role in the development of PH. In this review, we discuss some of the recent findings on the important interactive role and molecular mechanisms of mitochondrial ROS and Ca2+ in the development and progression of PH. We also address the contributions of NF-κB-dependent inflammatory responses and ketone-mediated oxidative stress due to abnormal regulation of mitochondrial ROS and Ca2+ signaling in PH.

show abstract

Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway

Cited by 23 publications

References 65 publications

Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

Melatonin Attenuates Dasatinib-Aggravated Hypoxic Pulmonary Hypertension via Inhibiting Pulmonary Vascular Remodeling

Important Functions and Molecular Mechanisms of Mitochondrial Redox Signaling in Pulmonary Hypertension

Contact Info

Product

Resources

About