Neuronal nitric oxide synthase in hypertension - an update

Abstract

Hypertension is a prevalent condition worldwide and is the key risk factor for fatal cardiovascular complications, such as stroke, sudden cardiac death and heart failure. Reduced bioavailability of nitric oxide (NO) in the endothelium is an important precursor for impaired vasodilation and hypertension. In the heart, NO deficiency deteriorates the adverse consequences of pressure-overload and causes cardiac hypertrophy, fibrosis and myocardial infarction which lead to fatal heart failure and sudden cardiac death. Recent consensus is that both endothelial and neuronal nitric oxide synthases (eNOS or NOS3 and nNOS or NOS1) are the constitutive sources of NO in the myocardium. Between the two, nNOS is the predominant isoform of NOS that controls intracellular Ca²⁺ homeostasis, myocyte contraction, relaxation and signaling pathways including nitroso-redox balance. Notably, our recent research indicates that cardiac eNOS protein is reduced but nNOS protein expression and activity are increased in hypertension. Furthermore, nNOS is induced by the interplay between angiotensin II (Ang II) type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R), mediated by NADPH oxidase and reactive oxygen species (ROS)-dependent eNOS activity in cardiac myocytes. nNOS, in turn, protects the heart from pathogenesis via positive lusitropy in hypertension. Soluble guanylate cyclase (sGC)-cGMP/PKG-dependent phosphorylation of myofilament proteins are novel targets of nNOS in hypertensive myocardium. In this short review, we will endeavor to overview new findings of the up-stream and downstream regulation of cardiac nNOS in hypertension, shed light on the underlying mechanisms which may be of therapeutic value in hypertensive cardiomyopathy.

Keywords: Cardiomyocyte; Hypertension; Hypertrophy; Neuronal nitric oxide synthase (nNOS); Nitric oxide.

Fig. 1

Structure of an active nNOS protein. Schematic diagram shows the two monomers of nNOS (each contains an oxygenase domain (−COOH terminal) and a reductase domain (−NH2 terminal). Electrons transfer from NADPH in the reductase domain of one monomar (via FDA and FMN) to the heme iron in the oxygenase domain of the other monomer, facilitated by calmodulin (CaM), enable nNOS to catalyze the oxidation of L-arginine to L-citrulline and releases NO. Ca²⁺ activates CaM and nNOS activity

Fig. 2

Schematic diagram of nNOS up-regulation by Ang II in cardiac myocytes and the potential target proteins, mechanism of regulation in cardiac myocytes from hypertension. Left. Ang II stimulates AT1R and NADPH oxidase in cardiac myocytes. AT1R and intracellular ROS activates Akt and phosphorylates endogeneous eNOS to produce NO. eNOS and NO-dependent S-nitrosation of AT2R lead to the translocation of AT2R to the plasma membrane and induces nNOS protein and increases NO production (data modified from Figure 8 of Basic Research in Cardiology, 2015, 110 (3):21). In hypertension, cardiac nNOS is up-regulated and facilitates myocyte relaxation. nNOS reduces Ca²⁺ influx via LTCC and promotes Ca²⁺ re-uptake via SERCA through PLN phosphorylation (secondary to PPase-dependent PKA phosphorylation) in healthy heart. In hypertension, nNOS inhibits LTCC and phosphorylates cMBP-C Ser²⁷³ and cTnI Ser^23/24 via cGMP/PKG-dependent mechanism. As a result, myofilament Ca²⁺ sensitivity is reduced which accounts for nNOS-dependent positive lusitropy in hypertension