Specific β1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia

Anne Sophie Arnold, Yao Liang Tang, Keping Qian, Leping Shen, Valery Valencia, Michael Ian Phillips, Yuan Clare Zhang

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

OBJECTIVES: β-blockers are widely used and effective for treating hypertension, acute myocardial infarction (MI) and heart failure, but they present side-effects mainly due to antagonism of β2-adrenergic receptor (AR). Currently available β-blockers are at best selective but not specific for β1 or β2-AR. METHODS: To specifically inhibit the expression of the β1-AR, we developed a small interfering RNA (siRNA) targeted to β1-AR. Three different sequences of β1 siRNA were delivered into C6-2B cells with 90% efficiency. RESULTS: One of the three sequences reduced the level of β1-AR mRNA by 70%. The siRNA was highly specific for β1-AR inhibition with no overlap with β2-AR. To test this in vivo, systemic injection of β1 siRNA complexed with liposomes resulted in efficient delivery into the heart, lung, kidney and liver, and effectively reduced β1-AR expression in the heart without altering β2-AR. β1 siRNA significantly lowered blood pressure of spontaneously hypertensive rats (SHR) for at least 12 days and reduced cardiac hypertrophy following a single injection. Pretreatment with β1 siRNA 3 days before induction of MI in Wistar rats significantly improved cardiac function, as demonstrated by dP/dt and electrocardiogram following the MI. The protective mechanism involved reduction of cardiomyocyte apoptosis in the β1 siRNA-treated hearts. CONCLUSIONS: The present study demonstrates the possibility of using siRNA for treating cardiovascular diseases and may represent a novel β-blocker specific for β1-AR.

Original languageEnglish (US)
Pages (from-to)197-205
Number of pages9
JournalJournal of hypertension
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 1 2007
Externally publishedYes

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Keywords

  • Blood pressure
  • Heart function
  • Myocardial infarction
  • RNA interference
  • β-adrenergic receptor
  • β-blockers

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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