Department of Surgery, Division of Cardiovascular Surgery, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
J Cardiovasc Transl Res. 2013 Apr;6(2):253-62. doi: 10.1007/s12265-012-9418-z. Epub 2012 Dec 1.
β-Adrenergic receptor (βAR) dysfunction in acute myocardial infarction (MI) is associated with elevated levels of the G-protein-coupled receptor kinase-2 (GRK2), which plays a key role in heart failure progression. Inhibition of GRK2 via expression of a peptide βARKct transferred by molecular cardiac surgery with recirculating delivery (MCARD) may be a promising intervention. Five sheep underwent scAAV6-mediated MCARD delivery of βARKct, and five received no treatment (control). After a 3-week period, the branch of the circumflex artery (OM1) was ligated. Quantitative PCR data showed intense βARKct expression in the left ventricle (LV). Circumferential fractional shortening was 23.4 ± 7.1 % (baseline) vs. -2.9 ± 5.2 % (p < 0.05) in the control at 10 weeks. In the MCARD-βARKct group, this parameter was close to baseline. The same trend was observed with LV wall thickening. Cardiac index fully recovered in the MCARD-βARKct group. LV end-diastolic volume and LV end-diastolic pressure did not differ in both groups. MCARD-mediated βARKct gene expression results in preservation of regional and global systolic function after acute MI without arresting progressive ventricular remodeling.
β-肾上腺素能受体（βAR）功能障碍与急性心肌梗死（MI）相关，其与 G 蛋白偶联受体激酶-2（GRK2）水平升高有关，而 GRK2 在心力衰竭进展中起关键作用。通过分子心脏手术与再循环输送（MCARD）表达的肽βARKct 来抑制 GRK2，可能是一种有前途的干预措施。五只绵羊接受了 scAAV6 介导的 MCARD 传递βARKct，而五只则未接受治疗（对照组）。经过 3 周后，结扎了回旋支动脉（OM1）。定量 PCR 数据显示左心室（LV）中βARKct 表达强烈。在第 10 周时，对照组的圆周分数缩短率为 23.4 ± 7.1％（基线）与 -2.9 ± 5.2％（p <0.05）。在 MCARD-βARKct 组中，该参数接近基线。LV 壁增厚也呈现出相同的趋势。MCARD-βARKct 组的心脏指数完全恢复。两组的 LV 舒张末期容积和 LV 舒张末期压力无差异。MCARD 介导的βARKct 基因表达可在急性 MI 后保持局部和整体收缩功能，而不会阻止进行性心室重构。
