Decreased expression of the cardiac LIM domain protein MLP in chronic human heart failure

Background-The cardiac LIM domain protein MLP, a member of the cysteine-ric h protein family, is an essential regulator of cardiac muscle development. Mice with a disruption of the MLP gene resemble the morphological and clini cal picture of dilated cardiomyopathy and heart failure in humans. We inves tigated whether altered MLP expression is significant for the pathogenesis of human heart failure. Methods and Results-Immunohistochemistry and in situ hybridization confirme d the expression of MLP protein and mRNA in human cardiomyocytes, Western b lot analysis revealed that the MLP peptide was present in the contractile p rotein fraction but not in the cytosolic or membrane fraction and that the binding of MLP to myofibrils required functional zinc finger domains. MLP i mmunoreactivity was decreased approximate to 50% (P<0.05) in the left ventr icular myocardium of patients with chronic heart failure due to dilated or ischemic cardiomyopathy compared with non-failing donor hearts. MLP mRNA ex pression, as assessed by Northern blot experiments, was not significantly d ifferent between failing and non-failing control hearts, which suggests tha t decreased MLP synthesis or increased MLP protein turnover, rather than a decreased number of RNA transcripts, may play a role. Conclusions-Because MLP may promote myofibril assembly, the down-regulation of this adapter protein might play an essential role in myofibril derangem ent or impaired myofibril rearrangement in the failing human myocardium.