AAV delivery of tumor necrosis factor-α short hairpin RNA attenuates cold-induced pulmonary hypertension and pulmonary arterial remodeling

Patrick Crosswhite, Kai Chen, Zhongjie Sun

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Cold temperatures are associated with increased mortality and morbidity of cardiovascular and pulmonary disease. Cold exposure causes lung inflammation, pulmonary hypertension (PH), and right ventricle hypertrophy, but there is no effective therapy because of unknown mechanism. Here, we investigated whether RNA interference silencing of tumor necrosis factor (TNF)-α decreases cold-induced macrophage infiltration, PH, and pulmonary arterial (PA) remodeling. We found for the first time that continuous cold exposure (5.0°C) increased TNF-α expression and macrophage infiltration in the lungs and PAs right before elevation of right ventricle systolic pressure. The in vivo RNA interference silencing of TNF-α was achieved by intravenous delivery of recombinant AAV-2 carrying TNF-α short hairpin small-interfering RNA 24 hours before cold exposure. Cold exposure for 8 weeks significantly increased right ventricle pressure compared with the warm controls (40.19±4.9 versus 22.9±1.1 mm Hg), indicating that cold exposure caused PH. Cold exposure increased TNF-α, interleukin-6, and phosphodiesterase-1C protein expression in the lungs and PAs and increased lung macrophage infiltration. Notably, TNF-α short hairpin small-interfering RNA prevented the coldinduced increases in TNF-α, interleukin-6, and phosphodiesterase-1C protein expression, abolished lung macrophage infiltration, and attenuated PH (26.28±1.6 mm Hg), PA remodeling, and right ventricle hypertrophy. PA smooth muscle cells isolated from cold-exposed animals showed increased intracellular superoxide levels and cell proliferation along with decreased intracellular cGMP. These cold-induced changes were prevented by TNF-α short hairpin small-interfering RNA. In conclusions, upregulation of TNF-α played a critical role in the pathogenesis of cold-induced PH by promoting pulmonary macrophage infiltration and inflammation. AAV delivery of TNF-α short hairpin small-interfering RNA may be an effective therapeutic approach for cold-induced PH and PA remodeling.

Original languageEnglish (US)
Pages (from-to)1141-1150
Number of pages10
JournalHypertension
Volume64
Issue number5
DOIs
StatePublished - Nov 1 2014

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Pulmonary Hypertension
Small Interfering RNA
Tumor Necrosis Factor-alpha
RNA Interference
Heart Ventricles
Lung
Macrophages
Phosphoric Diester Hydrolases
Hypertrophy
Vascular Remodeling
Interleukin-6
Pneumonia
Alveolar Macrophages
Superoxides
Lung Diseases
Smooth Muscle Myocytes
Proteins
Cardiovascular Diseases
Up-Regulation
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

AAV delivery of tumor necrosis factor-α short hairpin RNA attenuates cold-induced pulmonary hypertension and pulmonary arterial remodeling. / Crosswhite, Patrick; Chen, Kai; Sun, Zhongjie.

In: Hypertension, Vol. 64, No. 5, 01.11.2014, p. 1141-1150.

Research output: Contribution to journalArticle

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abstract = "Cold temperatures are associated with increased mortality and morbidity of cardiovascular and pulmonary disease. Cold exposure causes lung inflammation, pulmonary hypertension (PH), and right ventricle hypertrophy, but there is no effective therapy because of unknown mechanism. Here, we investigated whether RNA interference silencing of tumor necrosis factor (TNF)-α decreases cold-induced macrophage infiltration, PH, and pulmonary arterial (PA) remodeling. We found for the first time that continuous cold exposure (5.0°C) increased TNF-α expression and macrophage infiltration in the lungs and PAs right before elevation of right ventricle systolic pressure. The in vivo RNA interference silencing of TNF-α was achieved by intravenous delivery of recombinant AAV-2 carrying TNF-α short hairpin small-interfering RNA 24 hours before cold exposure. Cold exposure for 8 weeks significantly increased right ventricle pressure compared with the warm controls (40.19±4.9 versus 22.9±1.1 mm Hg), indicating that cold exposure caused PH. Cold exposure increased TNF-α, interleukin-6, and phosphodiesterase-1C protein expression in the lungs and PAs and increased lung macrophage infiltration. Notably, TNF-α short hairpin small-interfering RNA prevented the coldinduced increases in TNF-α, interleukin-6, and phosphodiesterase-1C protein expression, abolished lung macrophage infiltration, and attenuated PH (26.28±1.6 mm Hg), PA remodeling, and right ventricle hypertrophy. PA smooth muscle cells isolated from cold-exposed animals showed increased intracellular superoxide levels and cell proliferation along with decreased intracellular cGMP. These cold-induced changes were prevented by TNF-α short hairpin small-interfering RNA. In conclusions, upregulation of TNF-α played a critical role in the pathogenesis of cold-induced PH by promoting pulmonary macrophage infiltration and inflammation. AAV delivery of TNF-α short hairpin small-interfering RNA may be an effective therapeutic approach for cold-induced PH and PA remodeling.",
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