AAV-based RNAi silencing of NADPH oxidase gp91phox attenuates cold-induced cardiovascular dysfunction

Xiuqing Wang, Lucille Skelley, Bo Wang, Ayesha Mejia, Val Sapozhnikov, Zhongjie Sun

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Clinical observations and epidemiological surveys indicated that the prevalence of hypertension and heart diseases is increased in cold regions or during winter. Cold exposure increased NADPH oxidase gp91phox protein expression in heart, kidneys, and aorta in rats. The aim of this study was to investigate if RNA interference (RNAi) silencing of gp91phox would attenuate cold-induced hypertension and cardiovascular and renal damage. The recombinant adeno-associated virus serotype 2 (AAV-2) vector carrying gp91 phox-shRNA (gp91-shRNA) was constructed for inhibiting gp91 phox protein expression in cold-exposed rats. Blood pressure (BP) was monitored using a telemetry system. BP was increased in the Control-shRNA and PBS groups within 1 week of exposure to moderate cold (5°C) and reached a plateau after 7 weeks. The cold-induced increase in BP was attenuated significantly by intravenous delivery of gp91-shRNA (1.25×1010 particles/rat, 0.5â‰mL). One single dose of gp91-shRNA controlled hypertension for up to 10 weeks. In addition, gp91-shRNA reversed cold-induced vascular dysfunction. gp91-shRNA abolished the cold-induced up-regulation of gp91phox protein expression in heart, kidneys, and aorta, confirming effective silencing of gp91phox. The cold-induced increases in NADPH oxidase activity and superoxide production were eliminated by silencing of gp91phox, suggesting that the cold-induced up-regulation of NADPH oxidase activity may be attributed to the increased gp91phox protein expression. RNAi silencing of gp91phox abolished cold-induced cardiac and renal hypertrophy and attenuated aortic, coronary, and renal remodeling. The up-regulation of gp91phox may play a critical role in cold-induced cardiovascular dysfunction and organ damage. AAV delivery of gp91-shRNA may be a new and effective therapeutic approach for cold-related cardiovascular disorders.

Original languageEnglish (US)
Pages (from-to)1016-1026
Number of pages11
JournalHuman Gene Therapy
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2012

Fingerprint

NADPH Oxidase
RNA Interference
Small Interfering RNA
Kidney
Up-Regulation
Blood Pressure
Aorta
Proteins
Hypertension
Dependovirus
Telemetry
Renal Hypertension
Cardiomegaly
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one
Superoxides
Blood Vessels
Heart Diseases

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

AAV-based RNAi silencing of NADPH oxidase gp91phox attenuates cold-induced cardiovascular dysfunction. / Wang, Xiuqing; Skelley, Lucille; Wang, Bo; Mejia, Ayesha; Sapozhnikov, Val; Sun, Zhongjie.

In: Human Gene Therapy, Vol. 23, No. 9, 01.09.2012, p. 1016-1026.

Research output: Contribution to journalArticle

Wang, Xiuqing ; Skelley, Lucille ; Wang, Bo ; Mejia, Ayesha ; Sapozhnikov, Val ; Sun, Zhongjie. / AAV-based RNAi silencing of NADPH oxidase gp91phox attenuates cold-induced cardiovascular dysfunction. In: Human Gene Therapy. 2012 ; Vol. 23, No. 9. pp. 1016-1026.
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abstract = "Clinical observations and epidemiological surveys indicated that the prevalence of hypertension and heart diseases is increased in cold regions or during winter. Cold exposure increased NADPH oxidase gp91phox protein expression in heart, kidneys, and aorta in rats. The aim of this study was to investigate if RNA interference (RNAi) silencing of gp91phox would attenuate cold-induced hypertension and cardiovascular and renal damage. The recombinant adeno-associated virus serotype 2 (AAV-2) vector carrying gp91 phox-shRNA (gp91-shRNA) was constructed for inhibiting gp91 phox protein expression in cold-exposed rats. Blood pressure (BP) was monitored using a telemetry system. BP was increased in the Control-shRNA and PBS groups within 1 week of exposure to moderate cold (5°C) and reached a plateau after 7 weeks. The cold-induced increase in BP was attenuated significantly by intravenous delivery of gp91-shRNA (1.25×1010 particles/rat, 0.5{\^a}‰mL). One single dose of gp91-shRNA controlled hypertension for up to 10 weeks. In addition, gp91-shRNA reversed cold-induced vascular dysfunction. gp91-shRNA abolished the cold-induced up-regulation of gp91phox protein expression in heart, kidneys, and aorta, confirming effective silencing of gp91phox. The cold-induced increases in NADPH oxidase activity and superoxide production were eliminated by silencing of gp91phox, suggesting that the cold-induced up-regulation of NADPH oxidase activity may be attributed to the increased gp91phox protein expression. RNAi silencing of gp91phox abolished cold-induced cardiac and renal hypertrophy and attenuated aortic, coronary, and renal remodeling. The up-regulation of gp91phox may play a critical role in cold-induced cardiovascular dysfunction and organ damage. AAV delivery of gp91-shRNA may be a new and effective therapeutic approach for cold-related cardiovascular disorders.",
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