Superoxide Is Involved in the Central Nervous System Activation and Sympathoexcitation of Myocardial Infarction–Induced Heart Failure

Abstract

Increased angiotensin II signaling in the brain has been shown to play a critical role in the excessive sympathoexcitation and development of heart failure (HF) after myocardial infarction (MI). We have recently demonstrated that reactive oxygen species mediate the actions of angiotensin II in the brain. In this study, we tested the hypothesis that increased redox signaling in central cardiovascular control regions is a key mechanism in the neurocardiovascular dysregulation that follows MI. Ligation of the left coronary artery induced a large MI and subsequent HF in adult C57BL/6 mice, as demonstrated by cardiac hypertrophy, hydrothorax, and ascites. Immunohistochemical analysis of Fos, a marker of neuronal activation, revealed a significant increase in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 and 4 weeks after MI compared with sham mice. Intracerebroventricular injection of an adenoviral vector encoding superoxide dismutase (Ad-Cu/ZnSOD) caused a significant decrease in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 weeks after MI compared with mice receiving either saline or a control vector (Ad-LacZ). There was also a diminished role of sympathetic drive in post-MI mice treated centrally with Ad-Cu/ZnSOD, as demonstrated by significantly attenuated falls in heart rate and mean arterial pressure to the ganglionic blocker hexamethonium and decreased urinary norepinephrine levels in these mice compared with Ad-LacZ-treated MI mice. These results suggest that superoxide plays a key role in the central activation and sympathetic hyperactivity after MI in mice and that oxygen radicals in the brain may be important new targets for therapeutic treatment of heart failure.

Nox2, Ca 2+ , and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius

“…For example, Ang II-dependent systemic hypertension is associated with increased sympathetic nerve activity, 6 whereas Ang II-induced sympathoexcitation has also been linked to NADPH oxidase-derived ROS. [15][16][17][18] Thus, our findings suggest that Ang II-induced ROS production and L-type Ca 2ϩ currents might contribute to the central autonomic effects of Ang II. 9,58,59 Moreover, considering the well-established link among L-type Ca 2ϩ channels, ROS, and cellular plasticity, 60,61 heightened activation of AT 1 receptors in dmNTS neurons may also play a role in the reorganization of autonomic function accompanying hypertension.…”

“…10 -13 Within the dmNTS, activation of Ang II type 1 (AT 1 ) receptors alters cardiorespiratory reflexes including baroreceptor excitability and ion channel permeability. 10,14 These changes may contribute to Ang II-induced sympathoexcitation, [15][16][17][18] hypertension, 15,16 and heart failure. 17,18 Superoxide generated by the enzyme NADPH oxidase has emerged as a key intermediary in the central and peripheral effects of Ang II.…”

Cross talk between AT1receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

“…For example, ANG II-mediated ROS production within the PVN contributes to cardiovascular diseases with high sympathetic drive, such as hypertension and heart failure (9,43,59,74). However, the cellular sources and molecular targets involved in ANG II-ROS signaling dysregulation have not been fully elucidated.…”

Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

“…Sympathetic activation 29 and ROS [13][14][15][16][17][18] have been reported to lead not only to hypertension but also to organ damage. Therefore, sympathetic inhibition with an antioxidant can be a useful target for treatment of hypertension and its complications.…”