MDL-28170, a membrane-permeant calpain inhibitor, attenuates stunning and PKCε proteolysis in reperfused ferret hearts

Abstract

Mechanical stunning during R is sensitive to MDL-28170. Depressed mechanical function is reflected in a hyposensitization of trabecular myofilaments to Ca2+. Western analysis shows that PKM epsilon is present in R hearts.

Calpains: a physiological regulator of the endothelial barrier?

“…Thus hearts perfused only with buffer show no change in transudate formation. On the other hand, supplementing perfusate with either one of the calpain inhibitors, CI or CPP, caused a dramatic increase in postischemic transudate flow, quite the opposite of what we had expected on the basis of literature concerning cardioprotective actions of calpain inhibition (30,32). Even more surprising came the observation that calpain inhibitors increased coronary leak in control hearts not even subjected to ischemia, the time course of leak development (no instantaneous onset) being in good accordance with a process evolving from enzymatic inhibition.…”

Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload

“…Desmin has been reported to be degraded by calpain in ischemic rat hearts [28], although in right heart failure from neonatal hypoxic pulmonary hypertension desmin organization changes without degradation [34]. Other regulatory proteins such as SERCA2 [27]and PKC epsilon [13] have been reported to be substrates for calpain in other settings. Thus, the mechanism by which calpain affects contractile dysfunction appears to be highly variable.…”

“…Myocardial ischemia-reperfusion is also associated with calpain activation; the resulting "stunning" is attenuated by broad-spectrum cysteine protease inhibitors such as leupeptin [12], as well as by more specific calpain inhibitors [13,14]. By analogy, we hypothesized that RV pressure overload leads to activation of calpain, and that RV dysfunction would therefore be attenuated by administration of a calpain inhibitor.…”

Specific enhancement of sarcomeric response to Ca2+protects murine myocardium against ischemia-reperfusion dysfunction

“…Although the role of this proteolytic cleavage of cTnI appears to be more prominent in rats than in other species, there is general agreement that disturbance of the integrity of myofilament proteins such as proteolysis and oxidation is a major contributing factor to I/R (27). There is also the possibility that posttranslational modifications of sarcomeric proteins, which depress maximum myofilament tension, are associated with I/R-induced activation of kinases such as PKC (44) and the mitogen-activated protein kinase p38 MAP kinase (26).…”