Synergetic Antioxidant and Vasodilatory Action of Carbon Monoxide in Angiotensin II–Induced Cardiac Hypertrophy

Abstract

Abstract-The aim of this study was to determine the effects of carbon monoxide (CO) at a nontoxic low concentration on the cardiac and vascular hypertrophic response and reactive oxygen species generation, compared with the action of a vasodilator, hydralazine. Twelve-to 16-week-old low-density lipoprotein receptor knockout mice were subjected to angiotensin II (Ang II) infusion using osmotic minipumps (Ang II group; nϭ11) for 2 weeks. Controls were administered saline (nϭ10). Animals were exposed to CO in a chamber at 60 ppm for 2 hours per day with or without Ang II infusion (Ang IIϩCO group, nϭ10; CO group, nϭ9). Hydralazine was administered with Ang II infusion (nϭ10). Animals exhibited elevated arterial carboxyhemoglobin after CO exposure. Although the CO exposure did not affect systolic blood pressure without Ang II infusion, the hypertensive response after Ang II infusion was significantly attenuated by CO. Accordingly, the mice in the Ang IIϩCO group showed lesser left ventricular hypertrophy compared with those in the Ang II group. CO treatment also attenuated aortic hypertrophy. Interestingly, these changes were accompanied by the reduction of reactive oxygen species production, p47 phox and p67 phox subunit expressions of reduced nicotinamide-adenine dinucleotide phosphate oxidase, and Akt phosphorylation. Although hydralazine showed stronger antihypertensive action, superior inhibition on cardiac hypertrophy was obtained by CO (PϽ0.05). Furthermore, Ang IIdependent myocardial reactive oxygen species generation was more effectively suppressed by CO. Low-dose exogenous CO treatment attenuates Ang II-dependent reactive oxygen species generation, suggesting that appropriate CO administration alleviates hypertension and reduces organ hypertrophy mediated by Ang II. Key Words: carbon monoxide Ⅲ angiotensin II Ⅲ reactive oxygen species Ⅲ hyperlipidemia Ⅲ hypertension C arbon monoxide (CO), a low-molecular-weight diatomic gaseous molecule, has been considered a dangerous inhalation hazard, because CO binds to hemoglobin with high affinity. 1 CO arises primarily from the large-scale environment and human activities, such as volcanic emissions, forest fires, plant metabolisms, industrial processes, and exhaust emissions.However, recent studies have revealed that CO has profound effects on intracellular signaling processes. The physiological signaling effects of CO involve modulation of soluble guanylate cyclase and subsequent upregulation of cGMP production similar to those of NO. Additional mechanisms include the modulation of several mitogen-activated protein kinase activation pathways. 2,3 CO is endogenously produced during the processes of heme catabolism via heme oxygenase (HO). 4 Because protective roles of HO under various pathophysiological processes have been reported, 5-7 the roles of CO under these processes have currently drawn attention.The vasodilating properties of CO have been investigated in the cardiovascular system. 4,8 CO also has antiapoptotic 9 and anti-inflammatory 10 potentials. However...

Endogenous Carbon Monoxide Concentration in Blood Elevates in Acute Coronary Syndrome of Nonsmoker Population

“…CO also has antiapoptotic 2) and anti -inflammatory 3) potentials. In addition, we showed previously that CO also had antioxidative behavior 13) . Tobacco smoking is an important source of CO as a pollutant 15) .…”

“…Moreover, the vasodilatation properties of CO, which also has anti -apoptotic and anti -in-CARBON MONOXIDE ELEVATES IN ISCHEMIC HEART flammatory potentials 2,3) , have been investigated in the cardiovascular system 12) . We previously reported that synergetic antioxidant and vasodilatory action of carbon monoxide attenuated angiotensin IIinduced cardiac hypertrophic change 13) . Although the cytoprotective roles of CO has been investigated by in vitro studies using CO releasing molecules (11) and in vivo studies using high exogenous CO exposure 14) , the behavior of CO under pathophysiological conditions is still unknown.…”

Role of Carbon Monoxide in Blood Pressure Regulation

“…2,18 One limitation with CO inhalation is the high levels of blood carboxyhemoglobin (COHb) that are achieved at CO levels (200 to 500 ppm) required to ensure significant increases in tissue levels of CO. 19,20 These effects on blood COHb levels may limit the clinical applicability of CO inhalation unless lower levels of CO can achieve similar results. In support of this idea, a recent study by Kobayashi et al 21 demonstrated that low-level CO inhalation (60 ppm), which did not result in a dramatic increase in blood COHb levels, was able to significantly attenuate the development of angiotensin II (Ang II)-dependent hypertension. This study provides the first evidence that chronic low level CO inhalation may be a viable option for the treatment of hypertension.…”

“…This statement is especially true for CO, because levels as low as 800 ppm in the air can be fatal. However, a growing body of literature indicates that low-level CO inhalation (Ͻ100 ppm) or treatment with CO donors has several beneficial cardiovascular actions, including lowering of blood pressure, 21 protection against cardiac ischemia, 1,93 and protection against diabetes induced vascular injury. 25 There are also substantial reports that induction of HO-1, which results in increased CO production, also lowers blood pressure in several forms of hypertension.…”

Angiotensin II–Dependent Superoxide

“…Kobayashi et al 15 studied the effects of carbon monoxide (CO) because it reduces O 2 Ϫ and may ameliorate the pro-oxidant effects of Ang II. In Ang II-infused mice, CO administered for 2 hours per day attenuated the rise in BP and left ventricular hypertrophy compared with Ang II controls.…”