Pressure overload causes an accumulation of
homocysteine in the heart, which is accompanied by
copper depletion through the formation of
copper-
homocysteine complexes and the excretion of the complexes.
Copper supplementation recovers
cytochrome c oxidase (CCO) activity and promotes myocardial angiogenesis, along with the regression of
cardiac hypertrophy and the recovery of cardiac contractile function. Increased
copper availability is responsible for the recovery of CCO activity.
Copper promoted expression of angiogenesis factors including
vascular endothelial growth factor (
VEGF) in endothelial cells is responsible for angiogenesis.
VEGF receptor-2 (VEGFR-2) is critical for hypertrophic growth of cardiomyocytes and
VEGFR-1 is essential for the regression of cardiomyocyte
hypertrophy.
Copper, through promoting
VEGF production and suppressing
VEGFR-2, switches the
VEGF signaling pathway from VEGFR-2-dependent to VEGFR-1-dependent, leading to the regression of cardiomyocyte
hypertrophy.
Copper is also required for
hypoxia-inducible factor-1 (HIF-1) transcriptional activity, acting on the interaction between HIF-1 and the
hypoxia responsible
element and the formation of HIF-1 transcriptional complex by inhibiting the factor inhibiting HIF-1. Therefore, therapeutic targets for
copper supplementation-induced regression of
cardiac hypertrophy include: (1) the recovery of
copper availability for CCO and other critical cellular events; (2) the activation of HIF-1 transcriptional complex leading to the promotion of angiogenesis in the endothelial cells by
VEGF and other factors; (3) the activation of VEGFR-1-dependent regression signaling pathway in the cardiomyocytes; and (4) the inhibition of
VEGFR-2 through post-translational regulation in the hypertrophic cardiomyocytes. Future studies should focus on target-specific delivery of
copper for the development of clinical application.