Cobalt-Protoporphyrin Improves Heart Function by Blunting Oxidative Stress and Restoring NO Synthase Equilibrium in an Animal Model of Experimental Diabetes.

Myocardialdysfunctionandcoronarymacro/microvascularalterationsarethehallmarksofdiabeticcardiomyopathyandareascribedtoincreasedoxidativestressandalterednitricoxidesynhase(NOS)activity.Wehypothesizethatpre-treatmentbycobalt-protoporphyrinIX(CoPP)amelioratesbothmyocardialfunctionandcoronarycirculationinstreptozotocin(STZ)-induceddiabeticrats.IsolatedheartsfromdiabeticratsinLangendorffconfigurationdisplayedlowerleftventricularfunctionandhighercoronaryresistance(CR)comparedtoheartsfromcontrolanimals.CoPPtreatmentofdiabeticanimals(0.3mg/100gbodyweighti.p.,onceaweekfor3weeks)significantlyincreasedallthecontractile/relaxationindexes(p<0.01),whiledecreasingCR(p<0.01).CoPPenhancedHO-1proteinlevelsandreducedoxidativestressindiabeticanimals,asindicatedbythesignificant(p<0.05)decreaseinheart%GSSG,O−2,andmalondialdehyde(MDA)levels.CoPPincreasedadiponectinlevelsandphosphorylationofAKTandAMPKandreversedtheeNOS/iNOSexpressionimbal-anceobservedintheuntreateddiabeticheart.Furthermore,afterCoPPtreatment,ariseinmalonyl-CoAaswellasadecreaseinacetyl-CoAwasobservedindiabetichearts.Inthisexperimentalmodelofdiabeticcardiomyopathy,CoPPtreatmentimprovedbothcardiacfunctionandcoronaryflowbybluntingoxidativestress,restoringeNOS/iNOSexpres-sionbalanceandincreasingHO-1levels,therebyfavoringimprovementinbothendothelialfunctionandinsulinsensitivity.