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 language | English (US) |
|---|---|
| Pages (from-to) | 197-205 |
| Number of pages | 9 |
| Journal | Journal of Hypertension |
| Volume | 25 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2007 |
| Externally published | Yes |
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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
Cite this
Specific β1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia. / Arnold, Anne Sophie; Tang, Yao Liang; Qian, Keping; Shen, Leping; Valencia, Valery; Phillips, Michael Ian; Zhang, Yuan Clare.
In: Journal of Hypertension, Vol. 25, No. 1, 01.01.2007, p. 197-205.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Specific β1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia
AU - Arnold, Anne Sophie
AU - Tang, Yao Liang
AU - Qian, Keping
AU - Shen, Leping
AU - Valencia, Valery
AU - Phillips, Michael Ian
AU - Zhang, Yuan Clare
PY - 2007/1/1
Y1 - 2007/1/1
N2 - 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.
AB - 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.
KW - Blood pressure
KW - Heart function
KW - Myocardial infarction
KW - RNA interference
KW - β-adrenergic receptor
KW - β-blockers
UR - http://www.scopus.com/inward/record.url?scp=33845365806&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845365806&partnerID=8YFLogxK
U2 - 10.1097/01.hjh.0000254374.73241.ab
DO - 10.1097/01.hjh.0000254374.73241.ab
M3 - Article
C2 - 17143192
AN - SCOPUS:33845365806
VL - 25
SP - 197
EP - 205
JO - Journal of Hypertension
JF - Journal of Hypertension
SN - 0263-6352
IS - 1
ER -