Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload.
Right ventricular contractile failure from acute RV pressure overload is an important cause of morbidity and mortality, but the mechanism of RV failure in this setting is incompletely defined. We hypothesized that RV dysfunction from acute RV pressure overload is, in part, due to activation of calpain, and that calpain inhibition would therefore attenuate RV dysfunction. Anesthetized, open chest pigs were treated with the calpain inhibitor MDL-28170 or with inactive vehicle, and then subjected to acute RV pressure overload for 90 min. RV contractile function was assessed by the regional Frank-Starling relation. RV myocardial tissue was analyzed for evidence of calpain activation and calpain-mediated proteolysis. RV pressure overload caused severe contractile dysfunction, along with significant alterations in the endogenous calpain inhibitor calpastatin typical of calpain activation. MDL-28170 attenuated RV free wall dysfunction by more than 50%. However, there were no differences in degradation of spectrin, desmin, troponin-I or SERCA2 between SHAM operated pigs and pigs subjected to acute RV pressure overload, or between vehicle and MDL-28170 treated pigs. Acute RV pressure overload causes calpain activation, and RV contractile dysfunction from acute RV pressure overload is attenuated by the calpain inhibitor MDL-28170; however, the effect is not explained by inhibition of calpain-mediated degradation of spectrin, desmin, troponin-I or SERCA2. Because this is the first report of any agent that can directly attenuate RV contractile dysfunction in acute RV pressure overload, further investigation of the mechanism of action of MDL-28170 in this setting is warranted.
Greyson
Clifford R
CR
Cardiology Section, VA Medical Center and University of Colorado Health Sciences Center, Denver, CO 80220, USA. Clifford.Greyson@UCHSC.edu <Clifford.Greyson@UCHSC.edu>
Schwartz
Gregory G
GG
Lu
Li
L
Ye
Shuyu
S
Helmke
Steve
S
Xu
Ya
Y
Ahmad
Hasan
H
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003720:Densitometry; D003893:Desmin / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism; D013552:Swine; D014336:Troponin / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000201:enzymology* / Q000503:physiopathology*; D017725:Ventricular Pressure / Q000187:drug effects
D002135:Calcium-Binding Proteins; D003893:Desmin; D004151:Dipeptides; D014336:Troponin; D013049:Spectrin; C033668:calpastatin; D002154:Calpain; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C058076:calpain inhibitor III