Cardiac isoform of alpha-2 macroglobin, a novel serum protein, may induce cardiac hypertrophy in rats.

Earlier studies from this laboratory have identified a novel high molecular weight (182 kDa) serum protein suggested to be involved in the development of cardiac hypertrophy. In the present case the role of this novel serum protein in the development of pressure-induced cardiac hypertrophy and the molecular events associated with it in experimental rats has been investigated. Multiple injections of this purified protein intravenously (through tail vein) into the normal animals lead to the development of cardiac hypertrophy and this is accompanied by an induction of muscle specific genes such as that of MLC2 and beta-MHC characteristic of pressure overloaded heart. Further, the hypertrophy-specific serum protein has been found to be identical to rat alpha-2 macroglobulin (alpha-2M) in molecular weight (182 kDa) and in its appearance in blood serum. alpha-2M is an acute phase serum protein that increases markedly after inflammatory stimuli in hepatocytes in liver and gets secreted into the blood. The studies at present suggest that the 182kDa serum protein that appeared during the early stage of development of cardiac hypertrophy in aorta constricted rats is a glycoprotein localized in the heart that showed immunological cross reactivity with alpha-2M and is expressed in the heart as evinced by Northern blot analysis. Further this protein showed certain differences from rat alpha-2M under denaturing conditions in isoelectric focusing and partial peptide mapping. Partial peptide sequencing of the internal peptides of tryptic digest of 182 kDa showed 100% identity of the sequences with alpha-2M sequences. Rat alpha-2M does not, however, have any influence on the development of cardiac hypertrophy and its antibody does not cross react with the 182 kDa protein. These data suggest that the 182 kDa protein that may play an indispensable role in the development of cardiac hypertrophy in experimental rats is cardiac specific, and may be an isoform of liver alpha-2M belonging to macroglobulin family.