cDNA sequence and characterization of the gene that encodes human myotrophin/V-1 protein, a mediator of cardiac hypertrophy

The predominant response of the heart to sustained increased work load is d evelopment of ventricular hypertrophy, principally as a result of hypertrop hy of cardiomyocytes. The molecular mechanisms and factors involved in card iomyocyte hypertrophy are poorly understood, Myotrophin is a novel 12-kilod alton protein recently implicated as a factor associated with and able to i nduce cardiac hypertrophy. Cloning of rat myotrophin revealed that this pro tein is identical to the functionally undefined rat, murine and chicken V-l proteins. Although human myotrophin has been purified to homogeneity, its gene has not been characterized. In this report we describe the cloning, ex pression, purification and characterization of the human homolog of myotrop hin/V-1 protein. Sequence analysis indicaters high homology (>90%) between all species at both the nucleotide and amino acid levels, and Southern blot analysis of genomic DNA from diverse species verifies that myotrophin/V-1 is a highly conserved gene. Northern analysis indicates wide-spread express ion of a single human transcript, and examination of mRNA distribution in 5 0 human tissues by dot blot analysis indicates ubiquitous expression with r elatively high expressioon in adult and fetal heart. We verify that recombi nant human myotrophin produces cardiomyocyte hypertrophy, and we demonstrat e for the first time that elevated levels of myotrophin/V-1 protein mRNA ar e expressed in human dilated cardiomyopathic hearts. We report the novel fi ndings that myotrophin expression is elevated in ischemic hearts, and that myotrophin expression correlates positively with ventricular mass in a hypo xic rat model of induced right ventricular hypertrophy. (C) 1999 Academic P ress.