Figure 6.

Potential pathway underlying the anti-hypertrophic effect of CU-NP. As illustrated in (A), hypertrophic stimuli including PE, Ang II, and ET-1 activate NHE-1 via stimulation of their respective receptors (R). NHE-1 activation and the resultant increase in intracellular Na⁺ will elevate intracellular Ca²⁺ levels via the 3Na⁺–Ca²⁺ exchanger (NCX) either by slowing the removal of intracellular Ca²⁺ or driving the NCX in reverse. Elevated intracellular Ca²⁺ and the resulting Ca²⁺/calmodulin complex will activate calcineurin (CaN) which dephosphorylates the transcriptional factor NFAT resulting in its translocation into nuclei and subsequent up-regulation of genes related to hypertrophy including MCIP, ANP, and α-Sk actin (α-Sk). As proposed in (B), CU-NP (CU) acting via GCs/cGMP inhibits NHE-1, thus abrogating Ca²⁺/calmodulin-dependent calcineurin activation, dephosphorylation/translocation of NFAT, and the resultant hypertrophy.