Role of CO in the Carotid Body in Heart Failure

CO is known to be an important signaling molecule in the carotid body. CO, similarly to NO, plays a functional role in restraining hypoxic sensitivity of the carotid body in the normal condition and CO deficiency in the carotid body contributes to enhanced peripheral chemoreflex function and sympathetic activation in heart failure animals. The heme-oxygenase enzyme (HO) is the major pathway for CO production, and three isoforms of it have been identified, the inducible HO-1, the constitutive HO-2, and the HO-3 isoform with low enzymatic activity. CO increases intracellular levels of cGMP to promote vasodilation and also has anti-proliferative and anti-inflammatory properties. Ferrous iron can induce ferritin expression for iron sequestration. By generating these biologically active molecules and its upregulation in response to stress conditions, HO-1 acts to protect cells and tissues from oxidative stress-induced injury. HO-1 is upregulated in the failing heart. HO-1 gene delivery reduces mortality and improves left ventricular function in heart failure induced by coronary ligation in rats. Although HO is cardioprotective, its role in the carotid body in heart failure is less well defined. HO-2 is highly and constitutively expressed in neuronal and chemosensing tissues, including carotid body chemoreceptor (glomus) cells, but HO-1 is not. It has been found that HO-1 is not induced in the carotid body in heart failure animals, and surprisingly, HO-2 protein expression is markedly decreased in the carotid body. Furthermore, we found that the attenuated HO-2 activity in the carotid body of heart failure rabbits contributes to the enhanced chemoreflex function in heart failure. Several studies have assessed the functional significance of HO-2 in the carotid body in the normal state. Zn-protoporphyrin-9, an inhibitor of HO, augments the carotid body sensory discharge in vitro, and exogenous administration of CO can reverse the augmentation of sensory discharge induced by Zn-protoporphyrin-9. In the anesthetized rat, HO inhibition enhances respiratory responses to hypoxia but not to CO2, and the site of action is on the carotid body, since the effects of HO inhibition are abolished by bilateral section of the carotid sinus nerves. Similarly, the respiratory response to hypoxia is greater in mutant mice lacking the HO-2 isoform than in wild-type mice. It was suggested that HO-2 functions as an O₂ sensor by regulating K⁺ channel activity during hypoxia in carotid body cells, primarily through CO production. However, it was also observed that pharmacological inhibition of CO production enhances, rather than abolishes or suppresses, chemoreflex responsiveness to hypoxia. It has also been shown that there is a functional interaction between CO and NO pathways in the carotid body. Co-administration of CO + NO donors blunts the exaggerated hypoxia induced chemoreflex responses in heart failure rabbits to a greater extent than administration of either donor alone. Importantly, NO and CO share some common properties with O₂. 1) NO and CO bind to heme with greater affinity than O2 and are coupled to activation of heme-containing proteins. 2) NO and CO are involved in regulating intracellular Ca²⁺ concentration and the Ca²⁺-sensitive K⁺ channel in glomus cells. 3) Since NOS and HO-2 activities are sensitive to O₂ concentration and operate over a wide range of PO₂, both are capable of contributing to the O₂ sensitivity of the carotid body. 4) NO and CO responses are mediated by stimulation of cGMP production in many cells.