Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats

Ikeda, Yasuhiro; Yonemitsu, Yoshikazu; Kataoka, Chu; Kitamoto, Shiro; Yamaoka, Terutoshi; Nishida, Ken; Takeshita, Akira; Egashira, Kensuke; Sueishi, Katsuo

doi:10.1152/ajpheart.00919.2001

Cited by 101 publications

(82 citation statements)

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“…The CCL3 and CCL4 genes that code for monocyte/macrophage chemoattractant protein-1 alpha and beta (MCP-1a and MCP-1b), respectively, are of particular interest. Inhibition of these genes has been shown to prevent monocrotaline-induced pulmonary hypertension, suggesting a role for this chemokine in the pathogenesis of pulmonary vascular remodeling (32).…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate genes in scleroderma-related pulmonary arterial hypertension

Grigoryev

Mathai

Fisher

et al. 2008

Translational Research

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We hypothesize that pulmonary arterial hypertension (PAH)-associated genes identified by expression profiling of peripheral blood mononuclear cells (PBMCs) from patients with idiopathic pulmonary arterial hypertension (IPAH) can also be identified in PBMCs from scleroderma patients with PAH (PAH-SSc). Gene expression profiles of PBMCs collected from IPAH (n=9), PAH-SSc (n=10) patients and healthy controls (n=5) were generated using HG_U133A_2.0 GeneChips and processed by RMA/GCOS_1.4/SAM_1.21 data analysis pipeline. Disease severity in consecutive patients was assessed by functional status and hemodynamic measurements. The expression profiles were analyzed using PAH severity-stratification, and identified candidate genes were validated with real time PCR (rtPCR). Transcriptomics of PBMCs from IPAH patients was highly comparable with that of PMBCs from PAH-SSc patients. The PBMC gene expression patterns significantly correlate with right atrium pressure (RA) and cardiac index (CI), known predictors of survival in PAH. Array stratification by RA and CI identified 364 PAH-associated candidate genes. Gene ontology analysis revealed significant (Z score > 1.96) alterations in angiogenesis genes according to PAH severity: MMP9 and VEGF were significantly upregulated in mild as compared to severe PAH and healthy controls, as confirmed by rtPCR. These data demonstrate that PBMCs from patients with PAH-SSc carry distinct transcriptional expression. Furthermore, our findings suggest an association between angiogenesis-related gene expression and severity of PAH in PAH-SSc patients. Deciphering the role of genes involved in vascular remodeling and PAH development may reveal new treatment targets for this devastating disorder.

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Section: Discussionmentioning

confidence: 99%

Identification of candidate genes in scleroderma-related pulmonary arterial hypertension

Grigoryev

Mathai

Fisher

et al. 2008

Translational Research

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“…Adult male Sprague-Dawley rats (Charles River, Yokohama, Japan; 250 to 300 g body weight) were injected subcutaneously with 60 mg/kg MCT (Wako), which induces severe PAH in 3 weeks. 12,17 In a prevention protocol, animals were divided into 4 groups that received intratracheal instillation of phosphate-buffered saline (PBS), pitavastatin only (100 g), FITC-NP (1 mg PLGA), or pitavastatin-NP (100 g pitavastatin per mg PLGA) immediately after MCT injection. For intratracheal instillation, a 0.1-mL suspension of pitavastatin, FITC-NP, or pitavastatin-NP was injected gently into the trachea of animals, accompanied by an equal volume of air.…”

Section: Experimental Animal Modelsmentioning

confidence: 99%

“…RV systolic pressure and systemic blood pressure were measured with a polygraph system (AP-601G, Nihon Kohden). 12,17 Echocardiographic Measurements of RV and PA Hemodynamics…”

Section: Direct Rv Pressure Measurementsmentioning

confidence: 99%

“…Wet weight of the right ventricle and of the left ventricle plus ventricular septum was determined, and RV hypertrophy was expressed as RV weight/(left ventricle plus ventricular septum weights). 12,17 The lungs were perfused with a solution of 10% phosphatebuffered formalin (pH 7.4). At the same time, 10% phosphatebuffered formalin (pH 7.4) was administered into the lungs via tracheal tube at a pressure of 20 cm H 2 O.…”

Section: Assessment Of Right Heart Hypertrophy and Pa Remodelingmentioning

confidence: 99%

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Nanoparticle-Mediated Delivery of Pitavastatin Into Lungs Ameliorates the Development and Induces Regression of Monocrotaline-Induced Pulmonary Artery Hypertension

et al. 2011

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Abstract-Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH. Key Words: pulmonary hypertension Ⅲ nanotechnology Ⅲ pitavastatin Ⅲ inflammation Ⅲ leukocytes P ulmonary artery hypertension (PAH) is an intractable disease of the small PAs resulting in progressive increases in pulmonary vascular resistance, right ventricular (RV) failure, and ultimately premature death. 1,2 Mortality from PAH remains high, even after introduction of vasodilator therapies such as prostacyclin infusion, endothelin receptor antagonists, and phosphodiesterase inhibitors (which have raised the 5-year survival rate to Ϸ50%). Although these drugs were originally developed for non-PAH vascular diseases, they were introduced into treatment for clinical PAH on the basis of the vasodilator hypothesis. Therefore, a new idea that might lead to a breakthrough curative treatment for PAH is urgently needed.In addition to vasoconstriction, other multiple factors (endothelial injury/apoptosis, obstructive vascular remodeling, proliferation, and inflammation) play an important role in the mechanism of PAH. 1,2 Therefore, we hypothesized that a controlled, local delivery system targeting a battery of those pathogenic factors intrinsic to PAH pathology would be a favorable therapeutic approach with high translational potential to clinical medicine. In this respect, we focused on the vasculoprotective effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the so-called statins. Stati...

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“…Previously, studies have also shown that MCP-1 plays a role in monocrotaline-induced media hypertrophy. 29 Apparently, in the described flow-associated PAH model, MCP-1 is also activated by other factors than Egr-1. Interestingly though, perivascular macrophage infiltration, a known result of MCP-1 activation, was threefold higher after increased pulmonary blood flow (MϩF 30 versus M 30) and seen to be located around neointimal lesions.…”

Section: Egr-1 Transcription During Pulmonary Vascular Remodelingmentioning

confidence: 91%

Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension

Dickinson

Bartelds

Molema

et al. 2011

The American Journal of Pathology

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In flow-associated pulmonary arterial hypertension (PAH), increased pulmonary blood flow is an essential trigger for neointimal formation. Using microarray analysis, we recently found that the early growth response protein 1 (Egr-1) transcription factor is increased in experimental flow-associated end-stage PAH. Its role in PAH development is unknown. Here, we assessed the spatiotemporal expression of Egr-1 during neointimal development in flow-associated PAH. Flow-associated PAH was produced in rats by combining monocrotaline administration with an aortocaval shunt. Animals were sacrificed 1 day before or 1 day, 1 week, or 4 to 5 weeks after flow addition. Egr-1 expression was spatiotemporally assessed using laser microdissection, quantitative realtime PCR and immunohistochemistry. In addition, Egr-1 expression was assessed in a non-neointimal pulmonary hypertension model and in human PAH associated with congenital shunt. In 4 to 5 weeks, rats subjected to increased flow developed PAH with neointimal lesions. Egr-1 mRNA was increased 1 day after flow addition and in end-stage PAH, whereas monocrotaline only did not result in increased Egr-1 mRNA. Directly after flow addition, Egr-1 was expressed in endothelial cells. During disease development, Egr-1 protein expression increased and migrated throughout the vessel wall. In PAH patients, Egr-1 was expressed in vessels with media hypertrophy and neo- Pulmonary arterial hypertension (PAH) is a vasoproliferative disorder in which vascular obstruction of the small pulmonary arteries leads to an increased pulmonary vascular resistance and eventually death. 1 PAH is considered irreversible when pulmonary vascular remodeling is characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. 2,3 These neointimal lesions cause intraluminal obstruction arising from proliferation of endothelial and smooth muscle cells, fibrosis, and inflammation. 2,4,5 In congenital heart disease, increased pulmonary blood flow is an essential trigger for neointimal formation and disease development. Although neointimal development is well-described histopathologically, the pathogenesis of PAH and its typical vascular lesions is largely unknown. Several animal models have been described to investigate the pathogenesis of PAH. 6 The toxic alkaloid monocrotaline model is a commonly used experimental model of pulmonary hypertension. However, in this model neointimal lesions, typical for irreversible PAH, 3 are not seen. We and other investigators have shown that combining monocrotaline with an increased pulmonary blood flow results in pulmonary neointimal lesions in end-stage disease. [7][8][9][10] Little is known about the development of these lesions during disease progression.In a rat model of flow-associated PAH, we recently identified the early growth response protein 1 (Egr-1) transcription factor, by microarray analysis, to be upregulated in end-stage PAH only when increased pulmonary blood flow was added to monocrotalin...

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Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats

Cited by 101 publications

References 25 publications

Identification of candidate genes in scleroderma-related pulmonary arterial hypertension

Identification of candidate genes in scleroderma-related pulmonary arterial hypertension

Nanoparticle-Mediated Delivery of Pitavastatin Into Lungs Ameliorates the Development and Induces Regression of Monocrotaline-Induced Pulmonary Artery Hypertension

Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension

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