Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling

Kojonazarov, Baktybek; Sydykov, Akylbek; Pullamsetti, Soni Savai; Luitel, Himal; Dahal, Bhola K.; Kosanovic, Djuro; Tian, Xiaoling; Majewski, Matthäus; Baumann, Christin; Evans, Steve; Phillips, Peter G.; Fairman, David; Davie, Neil; Wayman, Chris; Kilty, Iain; Weißmann, Norbert; Seeger, Werner; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

doi:10.1016/j.ijcard.2012.06.129

Cited by 37 publications

(32 citation statements)

References 49 publications

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“…Measurement of transthoracic echocardiography was performed with the Vevo2100 high-resolution imaging system equipped with a 40-MHz transducer (VisualSonics, Toronto, Canada) (25). …”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing

Sommer

Hüttemann

Pak

et al. 2017

Circulation Research

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121

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Rationale Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing remains unresolved. Objectives To investigate the role of the pulmonary specific isoform 2 of subunit 4 of mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary oxygen sensing and signaling. Methods and Results Isolated ventilated and perfused lungs from Cox4i2−/− mice lacked acute HPV. In parallel, pulmonary arterial smooth muscle cells (PASMCs) from Cox4i2−/− mice showed no hypoxia-induced increase of intracellular calcium. Hypoxia-induced superoxide release which was detected by electron spin resonance spectroscopy in wild type (WT) PASMCs was absent in Cox4i2−/− PASMCs and was dependent on cysteine residues of Cox4i2. HPV could be inhibited by mitochondrial superoxide inhibitors proving functional relevance of superoxide release for HPV. Mitochondrial hyperpolarization, which can promote mitochondrial superoxide release, was detected during acute hypoxia in WT but not Cox4i2−/− PASMCs. Downstream signaling determined by patch clamp measurements showed decreased hypoxia-induced cellular membrane depolarization in Cox4i2−/− PASMCs compared to WT PASMCs, which could be normalized by application of hydrogen peroxide. In contrast, chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were not or only slightly affected by Cox4i2 deficiency, respectively. Conclusion Cox4i2 is essential for acute but not chronic pulmonary oxygen sensing by triggering mitochondrial hyperpolarization and release of mitochondrial superoxide which, after conversion to hydrogen peroxide, contributes to cellular membrane depolarization and HPV. These findings provide a new model for oxygen sensing processes in the lung and possibly also in other organs.

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“…Measurement of transthoracic echocardiography was performed with the Vevo2100 high-resolution imaging system equipped with a 40-MHz transducer (VisualSonics, Toronto, Canada) (25). …”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing

Sommer

Hüttemann

Pak

et al. 2017

Circulation Research

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121

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“…15 Microarray analysis RNA was extracted from whole right hearts of mice and converted, and samples were hybridized onto probe sets on an Illumina MouseRef-8v3 BeadChip array, as described elsewhere. 18 Data were analyzed using the syntax package R (ver.…”

Section: Echocardiographymentioning

confidence: 99%

The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy

et al. 2013

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Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator-activated receptor (PPAR) β/δ agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPARβ/δ is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have investigated the potential of GW0742, a PPARβ agonist, to act directly on the right heart in vivo and what transcriptomic signatures are associated with its actions. Right heart hypertrophy and failure was induced in mice using a pulmonary artery banding (PAB) model. GW0742 was administered throughout the study. Cardiovascular parameters were measured using echocardiography and pressure monitoring. Fibrosis and cellular changes were measured using immunohistochemistry. Transcriptomics were measured using the Illumina MouseRef-8v3 BeadChip array and analyzed using GeneSpring GX (ver. 11.0). PAB resulted in right heart hypertrophy and failure and in increased fibrosis. GW0742 reduced or prevented the effects of PAB on all parameters measured. GW0742 altered a number of genes in the transcriptome, with Angptl4 emerging as the top gene altered (increased) in animals with PAB. In conclusion, the PPARβ/δ agonist GW0742 has direct protective effects on the right heart in vivo. These observations identify PPARβ/δ as a viable therapeutic target to treat pulmonary hypertension that may complement current and future vasodilator drugs.

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“…It has been approved for the clinical treatment of advanced renal cell carcinoma, unresectable gastrointestinal stromal tumors, and well-differentiated metastatic pancreatic neuroendocrine tumors (Imbulgoda et al 2014). However, besides to its established clinical benefits for patients with a broad range of tumor types, recent studies have demonstrated that sunitinib reversed heart remodeling and significantly improved right ventricular function in experimental models of right ventricular hypertrophy (Kojonazarov et al 2013). Sunitinib was also reported to block collagen synthesis and mesenchymal transdifferentiation of human hepatic stellate cells, suggesting its potential as a drug candidate in pathological conditions like liver fibrosis (Majumder et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

Huang

Wang

Yuan

et al. 2016

Tohoku J. Exp. Med.

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Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition (EMT). However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin (BLM). Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells (HBEs) and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-β, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-β in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.

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Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling

Cited by 37 publications

References 49 publications

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing

The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

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