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Updated: Jun 10, 2026
A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
NF-kappaB driven cardioprotective gene programs; Hsp70.3 and cardioprotection after late ischemic preconditioning
Michael Tranter1, Xiaoping Ren, Tiffany Forde
1Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Insights
Nuclear factor-kappa B (NF-kappaB) regulates heat shock proteins, like Hsp70.3, which are crucial for heart protection after ischemic preconditioning (IPC). However, Hsp70.1 has opposing effects during ischemia/reperfusion injury.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Regulation
Background:
- Nuclear factor-kappa B (NF-kappaB) plays a dual role in cardiac ischemia/reperfusion (I/R) injury, being protective in late ischemic preconditioning (IPC) but detrimental in I/R.
- The specific downstream gene expression programs influenced by NF-kappaB in late IPC-mediated cardioprotection remain incompletely understood.
Purpose of the Study:
- To identify genes regulated by NF-kappaB immediately following late IPC.
- To validate methods for identifying NF-kappaB-dependent genes contributing to cardioprotection.
Main Methods:
- Directed microarray analysis to identify NF-kappaB-dependent gene expression changes 3.5 hours after late IPC.
- Gene ontological analysis to categorize the identified genes.
- Infarct size studies using Hsp70.1/70.3 double knockout and Hsp70.1 single knockout mouse models.
Main Results:
- Microarray analysis identified 238 NF-kappaB-dependent genes, including heat shock response genes like Hsp70.1 and Hsp70.3.
- Gene ontology revealed heat shock response genes as a major NF-kappaB-regulated category after late IPC.
- Hsp70.3 was confirmed as protective, while Hsp70.1/70.3 double knockout mice showed increased infarct size, and Hsp70.1 single knockout mice showed reduced infarct size after I/R.
Conclusions:
- This study delineates the immediate NF-kappaB-dependent transcriptome after late IPC, highlighting the heat shock response.
- Hsp70.3 contributes to cardioprotection, whereas Hsp70.1 and Hsp70.3 exhibit opposing functions during I/R injury despite coordinate regulation.
Abstract:
It has been shown that the transcription factor NF-kappaB is necessary for late phase cardioprotection after ischemic preconditioning (IPC) in the heart, and yet is injurious after ischemia/reperfusion (I/R). However the downstream gene expression programs that underlie the contribution of NF-kappaB to cardioprotection after late IPC are incompletely understood. The objective of this study was to delineate the specific genes that are regulated by NF-kappaB immediately after a late IPC stimulus and validate the methodology for the identification of NF-kappaB-dependent genes that contribute to cardioprotection. A directed microarray analysis identified 238 genes as up or downregulated in an NF-kappaB-dependent manner 3.5h after late IPC. Among these are several genes previously implicated in late IPC. Gene ontological analysis showed that the most significant group of NF-kappaB-dependent genes are heat shock response genes, including the genes encoding Hsp70.1 and Hsp70.3. Though an Hsp70.1/70.3 double knockout failed to exhibit cardioprotection, late IPC was intact in the Hsp70.1 single knockout. After I/R, the Hsp70.1/70.3 double knockout and the Hsp70.1 single knockout had significantly increased and reduced infarct size, respectively. These results delineate the immediate NF-kappaB-dependent transcriptome after late IPC. One of the major categories of NF-kappaB-dependent genes induced by late IPC is the heat shock response. The results of infarct studies confirm that Hsp70.3 is protective after IPC. However, though Hsp70.1 and Hsp70.3 are coordinately regulated, their functions are opposing after I/R injury.
