Hypoxia-induced mitochondrial reactive oxygen species (mtROS) differentially regulates smooth muscle cell (SMC) proliferation of pulmonary and systemic vasculature

Bhansali, Shipra; Sohi, Kamal; Dhawan, Veena

doi:10.1016/j.mito.2020.11.012

Cited by 11 publications

(4 citation statements)

References 26 publications

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“…Melatonin treatment significantly inhibited above-mentioned changes of PASMCs ( Figures 9A–E ). Except for NADPH oxidase, mitochondrial ROS is another crucial element that leads to oxidative stress ( 31 – 33 ). Similarly to the protein expression of SOD2 change, dasatinib in vitro treatment under hypoxia led to an increase in mitochondrial ROS production, melatonin reversed the increase in dasatinib-aggravated mitochondrial ROS production of PASMCs under hypoxia ( Figure 9F ).…”

Section: Resultsmentioning

confidence: 99%

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

Wang

Pan

Han

et al. 2022

Front. Cardiovasc. Med.

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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.

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Section: Resultsmentioning

confidence: 99%

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

Wang

Pan

Han

et al. 2022

Front. Cardiovasc. Med.

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“…3 and TableS2). Previous studies have shown that mitochondrial function inhibition is the key to the development of PAH [22]. Furthermore, it has never been studied how palmitoylation regulates the activity of mitochondrial transport proteins.…”

Section: Resultsmentioning

confidence: 99%

Cyclic guanosine monophosphate inhibits the palmitoylation of LETM1 and downregulates the activity of AKT in human pulmonary artery smooth muscle cells

Huang

Miao

et al. 2022

Preprint

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Cyclic guanosine monophosphate (cGMP) is a drug target for the treatment of pulmonary arterial hypertension (PAH). However, the molecular mechanism of cGMP in the pathogenesis of PAH remains unclear, and long-term use of cGMP target drugs leads to drug resistance. We tried to explore the new targets downstream of cGMP signaling and develop novel therapies for PAH. We combined mass spectrometry (MS)-based quantitative proteomics with click-chemistry-probes to identified palmitoylated candidate proteins. S-palmitoylation assay was ultilized to test whether the palmitoylation level of the candidates were regulated by cGMP. We identified palmitoylated proteins in human pulmonary artery smooth muscle cells (HPASMCs). Functional enrichment of the palmitoylated proteins showed that 52 proteins were involved in transmembrane transport, of which 7 were engaged in mitochondrial transport. S-palmitoylation assay in vitro demonstrated that the inner mitochondrial membrane protein, LETM1, was palmitoylated in the cytoplasmic domain at C-terminus. More importantly, cGMP could inhibit the palmitoylation level of LETM1, which in turn suppressed the activity of AKT regulated by LETM1. Our study found that the palmitoylation of LETM1 was the new target downstream of cGMP signaling. The palmitoylated site of LETM1 may provide a new direction for the development of novel therapies for PAH. Moreover, the palmitoylation level of LEMT1 may be a new biomarker for the analysis of prognosis.

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“…Finally, the 3,3′,5,5′‐tetramethylbenzidine peroxidase substrate (100 μL/well, 30 min, RT) was added followed by the addition of Stop solution (100 μL/well). Absorbance was measured at 450 and 550 nm via Bio‐Rad plate reader and net absorbance was calculated by subtracting the blank absorbance (Bhansali et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

PTEN‐AKT pathway attenuates apoptosis and adverse remodeling in ponatinib‐induced skeletal muscle toxicity following BMP‐7 treatment

Srivastava

Singla

2023

Physiological Reports

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Tyrosine kinase inhibitors (TKIs) including ponatinib are commonly used to treat cancer patients. Unfortunately, TKIs induce cardiac as well as skeletal muscle dysfunction as a side effect. Therefore, detailed mechanistic studies are required to understand its pathogenesis and to develop a therapeutic treatment. The current study was undertaken to examine whether ponatinib induces apoptosis and apoptotic mechanisms both in vitro and in vivo models and furthermore to test the potential of bone morphogenetic protein 7 (BMP-7) as a possible treatment option for its attenuation. Sol8 cells, a mouse myogenic cell line was exposed to ponatinib to generate an apoptotic cell culture model and were subsequently treated with BMP-7 to understand its protective effects. For the in vivo model, C57BL/6J mice were administered with ponatinib to understand apoptosis, cell signaling apoptotic mechanisms, and adverse muscle remodeling and its attenuation with BMP-7. TUNEL staining, immunohistochemistry (IHC), and real-time polymerase chain reaction (RT-PCR) methods were used. Our data show significantly (p < 0.05) increased TUNEL staining, caspase-3, BAX/Bcl2 ratio in the in vitro model. Furthermore, our in vivo muscle data show ponatinib-induced muscle myopathy, and loss in muscle function. The observed muscle myopathy was associated with increased apoptosis, caspase-3 staining, and BAX/Bcl-2 ratio as confirmed with IHC and RT-PCR. Furthermore, our data show a significant (p < 0.05) increase in the involvement of cell signaling apoptotic regulator protein PTEN and a decrease in cell survival protein AKT. These results suggest that increased apoptosis following ponatinib treatment showed an increase in skeletal muscle remodeling, sarcopenia, and fibrosis. Furthermore, BMP-7 treatment significantly (p < 0.05) attenuated ponatinib-induced apoptosis, BAX/Bcl2 ratio, decreased PTEN, and increased cell survival protein AKT, decreased adverse muscle remodeling, and improved muscle function. Overall, we provide evidence that ponatinib-induces apoptosis leading to sarcopenia and muscle myopathy with decreased function which was attenuated by BMP-7.

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Hypoxia-induced mitochondrial reactive oxygen species (mtROS) differentially regulates smooth muscle cell (SMC) proliferation of pulmonary and systemic vasculature

Cited by 11 publications

References 26 publications

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

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

Cyclic guanosine monophosphate inhibits the palmitoylation of LETM1 and downregulates the activity of AKT in human pulmonary artery smooth muscle cells

PTEN‐AKT pathway attenuates apoptosis and adverse remodeling in ponatinib‐induced skeletal muscle toxicity following BMP‐7 treatment

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