Carbonylation of myosin heavy chains in rat heart during diabetes.
Cardiac inotropy progressively declines during diabetes mellitus. To date, the molecular mechanisms underlying this defect remain incompletely characterized. This study tests the hypothesis that ventricular myosin heavy chains (MHC) undergo carbonylation by reactive carbonyl species (RCS) during diabetes and these modifications contribute to the inotropic decline. Male Sprague-Dawley rats were injected with streptozotocin (STZ). Fourteen days later the animals were divided into two groups: one group was treated with the RCS blocker aminoguanidine for 6 weeks, while the other group received no treatment. After 8 weeks of diabetes, cardiac ejection fraction, fractional shortening, left ventricular pressure development (+dP/dt) and myocyte shortening were decreased by 9%, 16%, 34% and 18%, respectively. Ca(2+)- and Mg(2+)-actomyosin ATPase activities and peak actomyosin syneresis were also reduced by 35%, 28%, and 72%. MHC-alpha to MHC-beta ratio was 12:88. Mass spectrometry and Western blots revealed the presence of carbonyl adducts on MHC-alpha and MHC-beta. Aminoguanidine treatment did not alter MHC composition, but it blunted formation of carbonyl adducts and decreases in actomyosin Ca(2+)-sensitive ATPase activity, syneresis, myocyte shortening, cardiac ejection fraction, fractional shortening and +dP/dt induced by diabetes. From these new data it can be concluded that in addition to isozyme switching, modification of MHC by RCS also contributes to the inotropic decline seen during diabetes.
Shao
Chun-Hong
CH
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, United States.
Rozanski
George J
GJ
Nagai
Ryoji
R
Stockdale
Frank E
FE
Patel
Kaushik P
KP
Wang
Mu
M
Singh
Jaipaul
J
Mayhan
William G
WG
Bidasee
Keshore R
KR
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006331:Heart Diseases / Q000378:metabolism*; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress; D050050:Protein Carbonylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin
D004791:Enzyme Inhibitors; D006146:Guanidines; D009942:Organometallic Compounds; D013311:Streptozocin; D018995:Myosin Heavy Chains; C004479:pimagedine