The Hopkins study, to be published in the May 2 edition of the Journal of Clinical Investigation, is believed to be the first to suggest future therapies for heart failure using chemical cofactors that control the enzymes' action.

Nitric oxide's extensive portfolio of natural effects includes the ability to expand coronary arteries, which improves blood flow, and to help regulate the strength of the heart's contraction, notes cardiologist David Kass, M.D., a specialist in enlarged hearts, or hypertrophy, and a professor at The Johns Hopkins University School of Medicine and its Heart Institute.

But there is clearly a dark side, a biological cost, to this activity in some situations when the enzyme changes form, Kass added.

In several experiments, the researchers simulated hypertrophy for up to nine weeks in groups of 10 to 40 male mice, some bred with and some bred without the gene for the most prominent of the NO-making enzymes, nitric-oxide synthase-3 (NOS3).

NOS3 stops functioning normally when levels of its cofactor, called tetrahydrobiopterin (BH4), decrease.

Results not only showed that BH4 levels drop in hypertrophied hearts, but also that NOS3 uncouples, or splits apart, in the absence of its cofactor. Less NO is produced, and instead, the enzyme produces factors that contribute to oxidative stress in the heart. When the researchers restored levels of BH4, it reversed these harmful effects.

In the first experiment, mice without NOS3 better compensated for the damaging stress of hypertrophy, showing less muscle growth, and fibrosis (scar tissue) and better heart function than mice with the enzyme.

Normal mice with the gene for NO
'"/>

Contact: David March
dmarch1@jhmi.edu
410-955-1534
Johns Hopkins Medical Institutions
26-Apr-2005