RIP3, a kinase promoting necroptotic cell death, mediates adverse remodeling after myocardial infarction.

Cardiovascular Research

PubMedID: 24920296

Luedde M, Lutz M, Carter N, Sosna J, Jacoby C, Vucur M, Gautheron J, Roderburg C, Borg N, Reisinger F, Hippe HJ, Linkermann A, Wolf MJ, Rose-John S, Lüllmann-Rauch R, Adam D, Flögel U, Heikenwaelder M, Luedde T, Frey N. RIP3, a kinase promoting necroptotic cell death, mediates adverse remodeling after myocardial infarction. Cardiovasc Res. 2014;103(2):206-16.
AIMS
Programmed necrosis (necroptosis) represents a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Like apoptosis, necroptosis is tightly regulated by distinct signalling pathways. A key regulatory role in programmed necrosis has been attributed to interactions of the receptor interacting kinases RIP1 and RIP3. However, the specific functional role of RIP3-dependent signalling and necroptosis in the heart is unknown. The aims of this study were thus to assess the significance of necroptosis and RIP3 in the context of myocardial ischemia.

METHODS AND RESULTS
Immunoblots revealed strong expression of RIP3 in murine hearts, indicating potential functional significance of this protein in the myocardium. Consistent with a role in promoting necroptosis, adenoviral overexpression of RIP3 in neonatal rat cardiomyocytes and stimulation with TNF-a induced formation of a complex of RIP1 and RIP3. Moreover, RIP3 overexpression was sufficient to induce necroptosis of cardiomyocytes. In vivo, cardiac expression of RIP3 was upregulated upon myocardial infarction. Conversely, mice deficient for RIP3 (RIP3(-/-)) showed a significantly better ejection fraction (45%±3.6% vs. 32%±4.4%, p<0.05) and less hypertrophy in MRI studies 30 days after experimental infarction due to LAD ligation. This was accompanied by a diminished inflammatory response of infarcted hearts and decreased generation of reactive oxygen species.

CONCLUSION
Here we show that RIP3-dependent necroptosis modulates post-ischemic adverse remodeling in a mouse model of myocardial infarction. This novel signalling pathway may thus be an attractive target for future therapies that aim to limit the adverse consequences of myocardial ischemia.