Increased expression of CAPON (Carboxy‐terminal PDZ ligand of nNOS) within the paraventricular nucleus (PVN) of rats with heart failure (HF).

Abstract

Activation of NMDA receptor initiates a Ca2+ influx that stimulates the production of NO by neuronal nitric oxide synthase (nNOS). A physical coupling of the NMDA receptor and nNOS occurs by an intermediary adaptor protein PSD95 (post synaptic density 95). CAPON, a protein rich in PVN competes with PSD95 for interaction with nNOS. Previously, we showed a decreased expression of nNOS and enhanced expression of NMDA NR1 within the PVN of rats with HF. To further elucidate the underlying mechanism of upregulation of NMDA NR1 with a concomitant downregulation of nNOS, we measured the levels of CAPON in left coronary ligation‐induced HF model of rats. CAPON expression is augmented by 22% in rats with HF. Previously we showed that Angiotensin II receptor (AT1) blocker, losartan (LOS) treatment in rats with HF normalized the changes in expression of NR1 and nNOS protein in the PVN. Consistent with these data, LOS treatment (10 mg/kg/day in the drinking water for three weeks) in rats with HF normalized protein expression of the CAPON in the PVN. Studies in neuronal NG108‐15 hybrid cell line treated with Ang II (6.25–100 μM) for 24h revealed 30% increase in CAPON expression at highest dose as compared to untreated cell samples. Co‐treatment with LOS (1μM) for 24h significantly, ameliorates the increased CAPON expression to Ang II. Immunostaining revealed colocalization of CAPON and nNOS in NG108 cell line as well as in PVN. These data suggest that perhaps the disparate changes in NR1 (upregulation) and nNOS (downregulation) may be due to an over expression of CAPON and this over expression of CAPON may be mediated by increased Ang II influence in rats with HF.