Nitroxyl (HNO) is a redox congener of NO. We now directly compare the antihypertrophic efficacy of HNO and NO donors in neonatal rat cardiomyocytes and compare their contributing mechanisms of actions in this setting.
Isopropylamine-NONOate (
IPA-NO) elicited concentration-dependent inhibition of
endothelin-1 (ET1)-induced increases in cardiomyocyte size, with similar suppression of hypertrophic genes. Antihypertrophic
IPA-NO actions were significantly attenuated by
l-cysteine (HNO scavenger), Rp-8-pCTP-cGMPS (
cGMP-dependent protein kinase inhibitor), and 1-H-(1,2,4)-oxodiazolo-quinxaline-1-one [ODQ; to target
soluble guanylyl cyclase (sGC)] but were unaffected by
carboxy-PTIO (NO scavenger) or
CGRP8-37 (
calcitonin gene-related peptide antagonist). Furthermore,
IPA-NO significantly increased cardiomyocyte cGMP 3.5-fold (an
l-cysteine-sensitive effect) and stimulated sGC activity threefold, without detectable NO release.
IPA-NO also suppressed ET1-induced cardiomyocyte
superoxide generation. The pure NO donor
diethylamine-NONOate (
DEA-NO) reproduced these
IPA-NO actions but was sensitive to
carboxy-PTIO rather than
l-cysteine. Although
IPA-NO stimulation of purified sGC was preserved under
pyrogallol oxidant stress (in direct contrast to
DEA-NO), cardiomyocyte sGC activity after either donor was attenuated by this stress. Excitingly
IPA-NO also exhibited acute antihypertrophic actions in response to pressure overload in the intact heart. Together these data strongly suggest that
IPA-NO protection against cardiomyocyte
hypertrophy is independent of both NO and CGRP but rather utilizes novel HNO activation of cGMP signaling. Thus HNO acutely limits
hypertrophy independently of NO, even under conditions of elevated
superoxide. Development of longer-acting HNO donors may thus represent an attractive new strategy for the treatment of
cardiac hypertrophy, as stand-alone and/or add-on
therapy to standard care.