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Jumonji (jmj) is the prototypical member of the jmj domain-containing protein family. It regulates the expression of several genes, in particular genes involved in cardiac cell growth in the embryonic heart. The function of jmj in the mature or developed heart, however, is unclear.We propose that JMJ domain 2A family may be involved in modulating the development of cardiac hypertrophy through interactions with cell cycle-regulatory proteins, specifically retinoblastoma protein, cyclin D and transcription factor E2F, that lead to cell growth. Because nitric oxide can block the development of cardiac hypertrophy and upregulate both jmj gene and protein expression, we propose that jmj is a novel regulatory factor mediating nitric oxide-induced modulation of cardiac hypertrophy.Jmj may be a critical, previously unrecognized factor that ‘counteracts’ the development of cardiac hypertrophy. Biotechnology approaches to increase its expression may be a potential therapeutic strategy to mitigate the increased cardiovascular morbidity and mortality associated with cardiac hypertrophy.