CONICET | Buscador de Institutos y Recursos Humanos

Dystrophin is responsible for the mechanical stabilization of thesarcolemma, and it has been shown that it is one of the most sensitiveproteins to ischemic injury. However, the enzyme responsible for thisproteolysis is still unknown. Isolated rabbit hearts were subjected to30 min of global ischemia with and without reperfusion (180 min) todetermine whether dystrophin is cleaved by matrix metalloproteinase(MMP)-2 during acute ischemia and whether ischemic preconditioning(PC) prevents dystrophin breakdown through MMP-2 inhibition.The activity of MMP-2 was evaluated by zymography and usingdoxycycline as an inhibitor. Also, to stimulate MMP-2 activity withoutischemia, SIN-1 was administered in the absence and presence ofdoxycycline. Finally, we considered the PC effect on MMP-2 activityand dystrophin expression. The dystrophin level decreased duringischemia, reaching 21% of control values (P 0.05), but the spectrinlevel remained unchanged. MMP-2 activity increased 71% duringischemia compared with control values (P 0.05). Doxycyclineadministration before ischemia prevented dystrophin breakdown. Innormoxic hearts, SIN-1 increased thiobarbituric acid-reactive substancesby 33% (P 0.05) and MMP-2 activity by 36% (P 0.05)and significantly reduced the dystrophin level to 23% of controlvalues (P 0.05). PC significantly prevented dystrophin breakdownby inhibiting MMP-2 activity, and the dystrophin level reached 89%of control values (P 0.05). In conclusion, MMP-2 could beresponsible for the proteolysis of dystrophin. Thus, dystrophinemerges as a possible novel substrate for MMP-2 in the context ofischemic injury. Furthermore, our results demonstrate that ischemicPC prevents dystrophin breakdown most likely by inhibiting MMP-2activity.