Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

THE S. SENLABORATORYPOSTDOCTORAL FELLOWSSudhiranjan Gupta, Ph.D.Pryan Prem, Ph.D.Sagartirtha Sarkar, Ph.D.TECHNICIANDavid YoungCOLLABORATORSOscar Bing, M.D., Ph.D. 1Joe Hollyfield, Ph.D. 2Anning Lin, Ph.D. 3Jun Qin, Ph.D. 4Mary Rayborn, M.S. 2Norman B. Ratliff, M.D. 5James D. Thomas, M.D. 6Qing Wang, Ph.D. 7M. Hilal Yamani, M.D. 61Dept. of Medicine, Tufts Univ.Sch. of Med., Boston, MA2Cole Eye Inst., CCF3Ben May Inst. for Cancer Res.,Univ. of Chicago, Chicago, IL4Dept. of Molecular Cardiology,CCF5Dept. of Anatomic Pathology,CCF6Dept. of Cardiovascular Medicine,CCF7Ctr. for Molecular Genetics, CCFYang, Y., Nanduri, S., Sen, S., and J. Qin (1998) The structural basis of ankyrin-like repeatfunction as revealed by the solution structure of myotrophin. Structure 6:619-626.Sen, S. (1999) Myocardial response to stress in cardiac hypertrophy and heart failure:effect of antihypertensive drugs. Ann. N.Y. Acad. Sci. 874:125-133.Mitra, S., Timur, A.A., Gupta, S., Wang, Q., and S. Sen (2001) Assignment of myotrophinto human chromosome band 7q33→q35 by in situ hybridization. Cytogenet. Cell Genet.93:151-152.Pathak, M., Sarkar, S., Vellaichamy, E., and S. Sen (2001) Role of myocytes in myocardialcollagen production. Hypertension 37:833-840.Gupta, S., Purcell, N.H., Lin, A., and S. Sen (2002) Activation of nuclear factor-κB isnecessary for myotrophin-induced cardiac hypertrophy. J. Cell Biol. 159:1019-1028.130Biochemical, Cellular, and Genetic StudiesReveal Molecular Aspects of MyocardialHypertrophyCardiac hypertrophy in hypertension, withsubsequent heart failure, is a major killerworldwide, whose causes remain unclear.Blood-pressure control mechanisms alone cannotexplain initiation/regression of such hypertrophy.We contend that it is initiated by (mechanicalor humoral) signals to the mycardium, whichin turn produce a factor that triggers proteinsynthesis.Since we first identified the 12-kDa proteinmyotrophin from hearts of spontaneously hypertensiverats (SHRs) and humans with myocardialhypertrophy, we have focused on why myotrophinlevels surge in hypertrophy. Webelieve myotrophin stimulatesmyocyte protein synthesis and maybe a common pathway for drugaction and workload stimulation.Recombinant myotrophinstimulates myocyte growth asactively as natural myotrophindoes. Myotrophin increasestranscript levels of protooncogenes(e.g., c-myc, c-fos, and c-jun) and known hypertrophymarkers (e.g., β-myosin heavychain, atrial natriuretic factor, andconnexin). Via radioimmunoassay,we found elevated myotro-phinlevels in hearts of SHRs andcardiomyopathic humans. Thesefindings demonstrate thatmyotrophin is a controlling factorfor myocyte growth.In 2000, we obtained exciting findings fromour newly established line of transgenic mice thatexpress myotrophin 10- to 100-fold normal,specifically in the heart, as measured by mRNA andproteins. Like humans, these mice exhibit leftventricular (LV) hypertrophy, cardiac myocytenecrosis, multiple focal fibrosis, and compromisedLV cardiac function with significantly reducedejection fraction. By 6 months, they develophypertrophy that worsens to heart failure, closelymimicking the human experience with cardiachypertrophy. This model provides a new investigationaltool to study molecular changes during thetransition of hypertrophy to failure.The Department of Molecular CardiologySubha Sen, Ph.D., D.Sc.Our laboratory combines molecular, genetic,and physiological approaches: (1) to define whatmolecular changes occur in these mice, thendetermine which changes result from myotrophinexcess; (2) to eludcidate myotrophin’s mechanism ofaction in vitro; and (3) by echocardiography, to definewhich cardiac functions correlate with observedmolecular changes.Our long-term goal is to understand howprotein synthesis is turned “on”/“off ” by selectivetherapy. We will then hold a key to therapeuticplanning for patients with hypertensive heartdisease, especially for developing appropriateantagonists to prevent/controlhuman cardiac hypertrophy.Collagen and Regression ofHypertrophyRegression of cardiovascularhypertrophy cannot beexplained by mechanical loadalone; it arises from the interplayof cardiac pressure load, thecardioadrenergic system, andvarious humoral factors.Each antihypertensive drughas a unique effect on thebiochemical composition ofcardiac collagen. Functionalconsequences vary according to thetype(s) of cardiac collagen ormyosin. Our focus is on cardiaccollagen production, determiningwhether regression of hypertrophyis beneficial or harmful.We hypothesize that functional/structuralremodeling of the heart’s interstitial matrix inhypertrophy and heart failure and the heart’s reremodelingafter regression reflect altered collagenproduction, which influences cardiac function. Westudy collagen phenotypes at the cellular andmolecular levels to evaluate their functionalconsequences.We recently identified fibroblast-derived factor(FDF), which stimulates angiotensin II (Ang II)-mediated myocyte growth. Ang II strongly stimulatesFDF secretion by fibroblasts, but its action canbe blocked by losartan, a specific Ang II receptorblocker. We were first to show that, via fibroblastmyocytecrosstalk, fibroblasts largely mediate AngII’s effect on myocyte growth. We are nowcharacterizing FDF and elucidating its mechanismsof action.These studies outline abnormalities duringdevelopment/regression of myocardial hypertrophyand explore effects on cardiac function. Oncederangements are found, we may suggest appropriatetreatments to correct changes in collagen formation/metabolism and evaluate whether directed alterationsin myocardial collagen formation can ameliorate thehypertrophied heart’s compromised function.