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Remote ischemic preconditioning prevents sarcolemmal-associated proteolysis by MMP-2 inhibition
Eliana P Bin1,2, Tamara Zaobornyj2,3, Mariana Garces2
1Universidad de Buenos Aires, Facultad de Ciencias Médicas, Instituto de Fisiopatología Cardiovascular, 950 J. E. Uriburu, 2nd floor, C1114AAD, Buenos Aires, Argentina.
Molecular and Cellular Biochemistry
|September 20, 2023
Summary
Remote ischemic preconditioning (rIPC) protects heart cells by preserving key structural proteins and improving mitochondrial function. This protection is achieved by inhibiting metalloproteinase type 2 (MMP-2) activity, reducing cell damage during reperfusion.
Area of Science:
- Cardiovascular Physiology
- Cellular Biology
- Biochemistry
Background:
- Myocyte death, particularly irreversible injury, is often marked by plasma membrane rupture.
- Structural proteins like dystrophin and β-dystroglycan are crucial for myocyte membrane stability.
- Metalloproteinase type 2 (MMP-2) activation contributes to sarcolemmal disruption following ischemia-reperfusion.
Purpose of the Study:
- To investigate if remote ischemic preconditioning (rIPC) preserves membrane-associated cytoskeletal proteins (dystrophin and β-dystroglycan).
- To determine if rIPC inhibits metalloproteinase type 2 (MMP-2) activity.
- To describe intracellular signaling pathways activated by rIPC that modify mitochondrial function during early reperfusion.
Main Methods:
- Isolated rat hearts subjected to global ischemia and reperfusion (I/R).
- rIPC applied via cycles of ischemia/reperfusion in the lower limb.
- Assessment of infarct size, Akt/GSK-3β phosphorylation, mitochondrial function, MMP-2 activity, and cytoskeletal protein integrity.
Main Results:
- rIPC significantly reduced infarct size and inhibited the mitochondrial permeability transition pore (MPTP) opening.
- rIPC improved mitochondrial function, evidenced by increased membrane potential, ATP production, and respiratory control.
- rIPC attenuated the breakdown of β-dystroglycan and dystrophin by inhibiting MMP-2 activity, which was activated by ischemia-reperfusion-induced ONOO⁻ production.
Conclusions:
- rIPC protects against ischemia-reperfusion injury by preserving sarcolemmal integrity through MMP-2 inhibition.
- rIPC enhances mitochondrial function via intracellular signaling pathways involving Akt/GSK3β and MPTP.
- rIPC represents a promising therapeutic strategy for mitigating cardiac damage.
