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Published on: June 14, 2016
TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways
Sandra B Haudek1, George E Taffet, Michael D Schneider
1Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Texas, USA.
Abstract:
Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl-2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t-Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.
Insights
Sustained TNF signaling causes heart failure by activating multiple cell death pathways. Overexpressing Bcl-2 partially protects against cardiac remodeling but doesn't fully prevent cardiomyocyte apoptosis.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Death Signaling
Background:
- Transgenic mice overexpressing TNF (MHCsTNF) exhibit adverse cardiac remodeling, including left ventricular (LV) wall thinning and dilation.
- This remodeling is associated with increased cardiomyocyte apoptosis and reduced levels of the anti-apoptotic protein Bcl-2.
Purpose of the Study:
- To investigate whether cardiac-restricted overexpression of Bcl-2 can prevent TNF-induced adverse cardiac remodeling.
- To elucidate the specific cell death pathways involved in TNF-mediated cardiac injury.
Main Methods:
- Crossed MHCsTNF mice with mice overexpressing Bcl-2 in the heart.
- Analyzed activation of intrinsic (cytochrome c, Smac/Diablo, Omi/HtrA2, caspases-3, -9) and extrinsic (c-FLIP, caspase-8, Bid, t-Bid) cell death pathways.
- Assessed left ventricular structure and cardiomyocyte apoptosis.
Main Results:
- Cardiac Bcl-2 overexpression blunted intrinsic pathway activation and prevented LV wall thinning.
- Bcl-2 overexpression only partially attenuated cardiomyocyte apoptosis.
- TNF signaling activated both intrinsic and extrinsic cell death pathways concurrently.
- Extrinsic pathway activation (caspase-8, t-Bid) was not affected by Bcl-2 overexpression.
Conclusions:
- Sustained inflammation activates multiple, parallel cell death pathways (intrinsic and extrinsic) in cardiomyocytes.
- Programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.
- While Bcl-2 offers partial protection, targeting multiple death pathways may be necessary for complete prevention of cardiac dysfunction.
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