TY - JOUR
T1 - β-Adrenergic receptor blockade modulates Bcl-XS expression and reduces apoptosis in failing myocardium
AU - Prabhu, Sumanth D.
AU - Wang, Guangwu
AU - Luo, Jianzhu
AU - Gu, Yan
AU - Ping, Peipei
AU - Chandrasekar, Bysani
N1 - Funding Information:
This work was supported by an Established Investigator Grant (S.D.P.) and Grant-In-Aid (B.C.) from the American Heart Association, NIH grants HL63901 and HL65431 (P.P.) and HL68020 (B.C.), a Merit Award from the Department of Veterans Affairs (S.D.P.), and the Commonwealth of Kentucky Research Challenge Trust Fund (S.D.P. and P.P).
PY - 2003/5/1
Y1 - 2003/5/1
N2 - The mechanisms by which β-adrenergic receptor (β-AR) blockade modulates apoptosis in heart failure (HF) are unclear. We examined the impact of β-AR blockade with metoprolol on myocardial remodeling, apoptosis, pro-apoptotic (Fas, Fas ligand, Bax, and Bcl-XS) and anti-apoptotic (Bcl-XLand Bcl-2) gene expression, and Bcl-XL and Bcl-XS protein in post-infarction HF in rats. In untreated rats, there was significant (P < 0.001) LV dilatation and systolic dysfunction compared to sham. Myocardial apoptosis was significantly increased (P < 0.005). Fas, Bax, and Bcl-2 mRNA expression was unchanged. However, Fas ligand mRNA and Bcl-XS mRNA and protein, all undetectable in sham, were markedly elevated (P < 0.001), whereas Bcl-XL mRNA and protein was unchanged. Immunohistochemistry confirmed increased Bcl-XS staining in failing myocardium, with unchanged Bcl-XL. Metoprolol treatment resulted in: (1) improved LV remodeling (P < 0.025), (2) reduced myocardial apoptosis (P < 0.005), and (3) selective reduction in myocardial Bcl-XS expression (P < 0.001) without change in Fas, Fas ligand, Bax, Bcl-2, or Bcl-XL. Studies in isolated rat myocytes revealed that prolonged isoproterenol (ISO) stimulation significantly increased Bcl-XS protein, reducing the Bcl-XL/XS ratio and myocyte survival (P < 0.005). ISO-induced Bcl-XS expression was significantly attenuated (P < 0.001) by both metoprolol and CGP20712A, a β1-AR selective antagonist, but not by ICI118,551, a β2-AR selective antagonist. We conclude that adrenergic activation, such as occurs in HF, increases pro-apoptotic Bcl-XS expression via the β1-AR. β-AR blockade in HF reduces myocardial apoptosis; attenuation of Bcl-XS expression may be one mechanism underlying this effect.
AB - The mechanisms by which β-adrenergic receptor (β-AR) blockade modulates apoptosis in heart failure (HF) are unclear. We examined the impact of β-AR blockade with metoprolol on myocardial remodeling, apoptosis, pro-apoptotic (Fas, Fas ligand, Bax, and Bcl-XS) and anti-apoptotic (Bcl-XLand Bcl-2) gene expression, and Bcl-XL and Bcl-XS protein in post-infarction HF in rats. In untreated rats, there was significant (P < 0.001) LV dilatation and systolic dysfunction compared to sham. Myocardial apoptosis was significantly increased (P < 0.005). Fas, Bax, and Bcl-2 mRNA expression was unchanged. However, Fas ligand mRNA and Bcl-XS mRNA and protein, all undetectable in sham, were markedly elevated (P < 0.001), whereas Bcl-XL mRNA and protein was unchanged. Immunohistochemistry confirmed increased Bcl-XS staining in failing myocardium, with unchanged Bcl-XL. Metoprolol treatment resulted in: (1) improved LV remodeling (P < 0.025), (2) reduced myocardial apoptosis (P < 0.005), and (3) selective reduction in myocardial Bcl-XS expression (P < 0.001) without change in Fas, Fas ligand, Bax, Bcl-2, or Bcl-XL. Studies in isolated rat myocytes revealed that prolonged isoproterenol (ISO) stimulation significantly increased Bcl-XS protein, reducing the Bcl-XL/XS ratio and myocyte survival (P < 0.005). ISO-induced Bcl-XS expression was significantly attenuated (P < 0.001) by both metoprolol and CGP20712A, a β1-AR selective antagonist, but not by ICI118,551, a β2-AR selective antagonist. We conclude that adrenergic activation, such as occurs in HF, increases pro-apoptotic Bcl-XS expression via the β1-AR. β-AR blockade in HF reduces myocardial apoptosis; attenuation of Bcl-XS expression may be one mechanism underlying this effect.
KW - Apoptosis
KW - Bcl-X
KW - Cell signaling
KW - Heart failure
KW - β-Adrenergic antagonists
UR - http://www.scopus.com/inward/record.url?scp=0038637913&partnerID=8YFLogxK
U2 - 10.1016/S0022-2828(03)00052-X
DO - 10.1016/S0022-2828(03)00052-X
M3 - Article
C2 - 12738230
AN - SCOPUS:0038637913
SN - 0022-2828
VL - 35
SP - 483
EP - 493
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 5
ER -