Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice
Abhinav Diwan, … , W. Keith Jones, Gerald W. Dorn II
Abhinav Diwan, … , W. Keith Jones, Gerald W. Dorn II
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2825-2833. https://doi.org/10.1172/JCI32490.
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Research Article

Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice

Abstract

Following myocardial infarction, nonischemic myocyte death results in infarct expansion, myocardial loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes ventricular remodeling in the mouse, despite having no effect on early or late infarct size. We evaluated the effects of ablating Bnip3 on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia/reperfusion (IR) injury in mice. Immediately following IR, no significant differences were observed between Bnip3–/– and WT mice. However, at 2 days after IR, apoptosis was diminished in Bnip3–/– periinfarct and remote myocardium, and at 3 weeks after IR, Bnip3–/– mice exhibited preserved LV systolic performance, diminished LV dilation, and decreased ventricular sphericalization. These results suggest myocardial salvage by inhibition of apoptosis. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice, causing progressive LV dilation and diminished systolic function. Conditional Bnip3 overexpression prior to coronary ligation increased apoptosis and infarct size. These studies identify postischemic apoptosis by myocardial Bnip3 as a major determinant of ventricular remodeling in the infarcted heart, suggesting that Bnip3 may be an attractive therapeutic target.

Authors

Abhinav Diwan, Maike Krenz, Faisal M. Syed, Janaka Wansapura, Xiaoping Ren, Andrew G. Koesters, Hairong Li, Lorrie A. Kirshenbaum, Harvey S. Hahn, Jeffrey Robbins, W. Keith Jones, Gerald W. Dorn II

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Figure 1

Generation and baseline characteristics of Bnip3-null mice.

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Generation and baseline characteristics of Bnip3-null mice. ...
(A) Schematic of Bnip3 deletion strategy depicting locations of exons 1–6 (black boxes), restriction sites, probe used for Southern blotting (Spe probe), and PCR primers (a–c). (B) Southern blot (left) and PCR (right) screening of Bnip3-targeted mice. (C) Bnip3 multiple tissue Northern blot (left) and immunoblot analysis of mitochondria-enriched myocardial protein (right). (D) Fluorescence cytometry of erythroid Ter119 and CD71 expression in splenocytes. Yellow represents proerythroblasts; blue, basophilic erythroblasts; pink, chromatophilic erythroblasts; green, orthochromatic erythroblasts. (E) Fluorescence cytometry of Gr-1 (granulocyte) and Mac-1 (macrophage) expression in bone marrow cells. (F) Masson trichrome–stained coronal heart sections. (G) M-mode echocardiograms; short-axis view of LV. (H) Invasive hemodynamic analysis of LV contractility at baseline and in response to β-adrenergic agonist dobutamine (n = 4, WT; n = 8, Bnip3–/–).