Leptin is a 16 kDa product of the
obesity gene secreted primarily by adipocytes. We recently identified cardiomyocytes as a target for the direct hypertrophic effects of
leptin and suggested that
leptin may be a biological link between
obesity and cardiovascular pathologies. Activation of the
renin-
angiotensin and
endothelin systems is associated with development of
cardiovascular diseases and plasma
renin levels are elevated in obese individuals. We therefore determined possible interaction between these factors in mediating
hypertrophy in cultured neonatal rat ventricular myocytes. Treatment for 24 h with
leptin (3.1 nM),
angiotensin II (100 nM) or
endothelin-1 (ET-1, 10 nM) significantly increased cell area by 37%, 36% and 35%, respectively and significantly increased gene expression of
myosin light chain-2 and alpha-skeletal actin as well as
leucine incorporation. The hypertrophic effects of all three agents were prevented by
leptin and a
leptin triple mutant receptor antagonist whereas the AT(1) receptor blocker (Sar1-lle(8))-Ang II or the ET(A) receptor blocker
BQ123 was ineffective against
leptin-induced
hypertrophy. Both
angiotensin II and ET-1 significantly increased
leptin levels in the culture medium by fivefold. Moreover, both
angiotensin II and ET-1 increased the gene expression of the short form (OBRa) by 180% and long form (OBRb) of
leptin receptors by 200%, and this increase was abolished by both
leptin receptor and
leptin antibodies and
leptin triple mutant. Although both
angiotensin II and ET-1 increased phosphorylation of
MAPK (p38, ERK1/2 and JNK) and
NF-kappaB, the ability of
leptin blockade to attenuate the hypertrophic responses was generally dissociated from these effects suggesting an alternate, yet to be identified cellular pathway mediating this role of
leptin. Our studies therefore suggest a novel autocrine function for
leptin in mediating the hypertrophic effects of both
angiotensin II and ET-1 in cardiac myocytes.