TY - JOUR
T1 - Carbonylation of myosin heavy chains in rat heart during diabetes
AU - Shao, Chun Hong
AU - Rozanski, George J.
AU - Nagai, Ryoji
AU - Stockdale, Frank E.
AU - Patel, Kaushik P.
AU - Wang, Mu
AU - Singh, Jaipaul
AU - Mayhan, William G.
AU - Bidasee, Keshore R.
N1 - Funding Information:
This work was supported in part by grants from the Edna Ittner Research Foundation (K.R.B), American Diabetes Association (K.R.B), National Institutes of Health NS-39751 (K.P.P), HL-066446 (G.J.R), HL 090657 and AA 01128 (W.G.M) and HL085061 (K.R.B) and Grant-in-Aid from the Ministry of Education, Science, Sports and Cultures of Japan (Scientific Research grant # 18790619 , R.N).
PY - 2010/7
Y1 - 2010/7
N2 - 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. Ca2+- and Mg2+-actomyosin ATPase activities and peak actomyosin syneresis were also reduced by 35%, 28%, and 72%. MHC-α to MHC-β ratio was 12:88. Mass spectrometry and Western blots revealed the presence of carbonyl adducts on MHC-α and MHC-β. Aminoguanidine treatment did not alter MHC composition, but it blunted formation of carbonyl adducts and decreases in actomyosin Ca2+-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.
AB - 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. Ca2+- and Mg2+-actomyosin ATPase activities and peak actomyosin syneresis were also reduced by 35%, 28%, and 72%. MHC-α to MHC-β ratio was 12:88. Mass spectrometry and Western blots revealed the presence of carbonyl adducts on MHC-α and MHC-β. Aminoguanidine treatment did not alter MHC composition, but it blunted formation of carbonyl adducts and decreases in actomyosin Ca2+-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.
KW - Carbonyl adducts
KW - Contractility
KW - Diabetes
KW - Myosin heavy chain
KW - Rat
KW - Reactive carbonyl species
KW - Streptozotocin
UR - http://www.scopus.com/inward/record.url?scp=77952670724&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2010.03.024
DO - 10.1016/j.bcp.2010.03.024
M3 - Article
C2 - 20359464
AN - SCOPUS:77952670724
SN - 0006-2952
VL - 80
SP - 205
EP - 217
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 2
ER -