Mitochondrial Respiratory Enzyme Complexes in Rostral Ventrolateral Medulla as Cellular Targets of Nitric Oxide and Superoxide Interaction in the Antagonism of Antihypertensive Action of eNOS Transgene

Abstract

Overproduction of nitric oxide (NO) by gene transduction of endothelial NO synthase (eNOS) in rostral ventrolateral medulla (RVLM), which is responsible for maintenance of vasomotor tone, reduces arterial pressure in spontaneously hypertensive rats (SHR). This NO-induced vasodepression, however, is not sustained and is followed by rebound hypertension. Because superoxide anion (O 2 . ) level is increased and synthesis or activity of mitochondrial manganese superoxide dismutase (SOD2) is reduced in RVLM during hypertension, we hypothesized that an interaction between NO and O 2 . in RVLM, using mitochondrial respiratory enzyme complexes (MRC) as the cellular target, contributes to those cardiovascular outcomes after eNOS gene transduction in SHR. The present study assessed this hypothesis using adenoviral vectors to overexpress eNOS (AdeNOS) and/or SOD2 (AdSOD2) in RVLM of SHR or normo- Nitric oxide (NO) is a gaseous molecule that plays an active role in central cardiovascular regulation (Zanzinger, 1999). One brain region in which NO is of pivotal importance in this regulatory machinery is the rostral ventrolateral medulla (RVLM) (Chan et al., 2001;Mayorov, 2005), which provides tonic sympathetic outflow for the maintenance of vasomotor tone (Dampney, 1994). Accumulating evidence suggests that NO deficiency in the RVLM may underlie sympathetic overexcitation (Kagiyama et al., 1998;Chan et al., 2003; TandaiHiruma et al., 2005) or impaired baroreflex regulation (Kishi et al., 2003) during hypertension. Accordingly, overproduction of NO by gene transduction of endothelial nitric-oxide

Redox-Sensitive Oxidation and Phosphorylation of PTEN Contribute to Enhanced Activation of PI3K/Akt Signaling in Rostral Ventrolateral Medulla and Neurogenic Hypertension in Spontaneously Hypertensive Rats

“…As a routine, microinjection sites were visually verified and recorded after the slice of medulla oblongata that contains RVLM (0.5-1.5 mm rostral to the obex) was obtained. Tissues from both sides of the ventrolateral medulla covering RVLM (1.5-to 2.5-mm lateral to the midline and medial to the spinal trigeminal tract) were collected by micropunches with a 1-mm inner diameter burr (2)(3)(4)(5)(6)27). Medullary samples within the boundaries of RVLM thus obtained from five to eight rats under the same experimental treatment were pooled to provide sufficient tissue for protein extraction.…”

Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

“…Furthermore, iNOS expression levels were increased in the RVLM of SHRSP compared with WKY (56). Kung et al (68) suggested that mitochondrial respiratory enzyme complexes in the RVLM were cellular targets of NO and ROS interaction after eNOS gene transfer. This concept is problematic, however, in that they suggest that superoxide and per- oxynitrite are produced after eNOS gene transfer into the RVLM (68).…”

“…Kung et al (68) suggested that mitochondrial respiratory enzyme complexes in the RVLM were cellular targets of NO and ROS interaction after eNOS gene transfer. This concept is problematic, however, in that they suggest that superoxide and per- oxynitrite are produced after eNOS gene transfer into the RVLM (68). Another recent study suggested that NMDA receptor activation increases ROS production through NO and Nox2 (33).…”

Approaches in Gene Therapy of Cancer and Cardiovascular Diseases

“…Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO and superoxide generation, which in turn has ramifications for the development of an endothelial dysfunction (Doughan et al, 2008). In the brain stem cardiovascular neurons in the RVLM, mitochondrial superoxide mediates the rebound hypertension induced by the eNOS transgene in SHR (Kung et al, 2008). Mice lacking iNOS (-/-) exhibits extensive cytoplasmic swelling and degeneration of mitochondria, decrease in the resting indices of cardiac function as well as an impairment in the positive inotropic actions of isoproterenol following treatment with adriamycin compared to nTg mice.…”

“…SOD enzymes therefore play an important role in cardiovascular tissue by protecting NO against oxidative inactivation by superoxide and they are important in vasodilatation and in the protection of NO bioactivity in blood vessel walls (Gongora & Harrison, 2008). Gene transduction of individual SOD genes (Chu et al, 2003;Zimmerman et al, 2004;Dovinova et al, 2008;Kamezaki et al, 2008) or combination of both SOD and NOS transgenes (Kung et al, 2008,) has positive influence on experimental hypertension. This protective effect is the end results of an increase in tissue level of NO and the decreases in oxidative stress (Chan et al, 2006) and peroxynitrite production (a cytotoxic molecule generated by reaction between superoxide and NO) (Kishi et al, 2004).…”