Attenuating development of atherosclerosis
[including coronary artery disease and peripheral vascular disease] and diabetes

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Hyperbaric oxygen induces a cytoprotective and angiogenic response in human microvascular endothelial cells
Godman CA, Chheda KP, Hightower LE, Perdrizet G, Shin DG, Giardina C.
Cell Stress Chaperones. 2010 Jul; 15(4):431-42. Epub 2009 Dec 1.

A genome-wide microarray analysis of gene expression was carried out on human microvascular endothelial cells (HMEC-1) exposed to hyperbaric oxygen treatment (HBOT) under conditions that approximated clinical settings. Highly up-regulated genes included immediate early transcription factors (FOS, FOSB, and JUNB) and metallothioneins. Six molecular chaperones were also up-regulated immediately following HBOT, and all of these have been implicated in protein damage control.

Pathway analysis programs identified the Nrf-2-mediated oxidative stress response as one of the primary responders to HBOT. Several of the microarray changes in the Nrf2 pathway and a molecular chaperone were validated using quantitative PCR. For all of the genes tested (Nrf2, HMOX1, HSPA1A, M1A, ACTC1, and FOS), HBOT elicited large responses, whereas changes were minimal following treatment with 100% O2 in the absence of elevated pressure. The increased expression of immediate early and cytoprotective genes corresponded with an HBOT-induced increase in cell proliferation and oxidative stress resistance.

In addition, HBOT treatment enhanced endothelial tube formation on Matrigel plates, with particularly dramatic effects observed following two daily HBO treatments. Understanding how HBOT influences gene expression changes in endothelial cells may be beneficial for improving current HBOT-based wound-healing protocols.

These data also point to other potential HBOT applications where stimulating protection and repair of the endothelium would be beneficial, such as patient preconditioning prior to major surgery.

Electronic supplementary material:
The online version of this article (doi:10.1007/s12192-009-0159-0) contains supplementary material, which is available to authorized users.

Hyperbaric oxygen treatment induces antioxidant gene expression
Godman CA, Joshi R, Giardina C, Perdrizet G, Hightower LE.
Ann N Y Acad Sci. 2010 Jun;1197:178-83. doi: 10.1111/j.1749-6632.2009.05393.x.

Although the underlying molecular causes of aging are not entirely clear, hormetic agents like exercise, heat, and calorie restriction may generate a mild pro-oxidant stress that induces cell protective responses to promote healthy aging.

As an individual ages, many cellular and physiological processes decline, including wound healing and reparative angiogenesis. This is particularly critical in patients with chronic non-healing wounds who tend to be older.

We are interested in the potential beneficial effects of hyperbaric oxygen as a mild hormetic stress on human microvascular endothelial cells. We analyzed global gene expression changes in human endothelial cells following a hyperbaric exposure comparable to a clinical treatment.

Our analysis revealed an upregulation of antioxidant, cytoprotective, and immediate early genes. This increase coincided with an increased resistance to a lethal oxidative stress.

Our data indicate that hyperbaric oxygen can induce protection against oxidative insults in endothelial cells and may provide an easily administered hormetic treatment to help promote healthy aging.

Hyperbaric oxygen: its application in cardiology: a historical perspective and personal journey
Ellestad MH.
Cardiol Rev. 2009 Nov-Dec; 17(6):280-2.

Hyperbaric oxygen (HBO) was first used by placing a patient with the “bends” in a pressure chamber and increasing the pressure to 3 atm with 100% oxygen. It was soon recognized that HBO could also facilitate wound healing in infected ischemic extremities. Before the pump oxygenator was developed, it was also shown to facilitate corrective surgery, especially in congenital heart disease.

In 1997, after encouraging animal work, HBO therapy was used in conjunction with thrombolytics to reduce the magnitude of injury in patients with acute myocardial infarction. The benefit is probably due to the decrease in reperfusion injury, which has been shown to be a major cause of myocardial cell death when the culprit artery is opened with a catheter. The most recent development is to infuse saline saturated with HBO into the opened coronary artery immediately after angioplasty. An advantage of this treatment has been demonstrated in experimental animals and in man.

Future applications of HBO treatment in cardiovascular disease await more research, but at this time it seems to have considerable promise.

The effect of hyperbaric oxygen therapy on blood vessel function in diabetes mellitus
Unfirer S, Kibel A, Drenjancevic-Peric I.
Med Hypotheses. 2008 Nov; 71(5):776-80. Epub 2008 Aug 22.

Prolonged untreated diabetes mellitus leads to microangiopathy, tissue hypoxia and ischemic lesions; it increases the risk for stroke and exacerbates brain tissue damage following ischemia. Patients exhibit advanced atherosclerosis in coronary and cerebral arteries as well as enhanced vascular responsiveness to vasoconstrictors, an attenuated response to vasodilators and impaired autoregulation of cerebral blood flow. Altered endothelial function of arterioles and an impaired vasomotor function of resistance vessels could contribute to altered regulation of regional blood flow and insufficient tissue perfusion in diabetes mellitus.

Hyperbaric oxygen therapy is shown to contribute to the healing of ischemic ulcerations in diabetic patients and to improvement of several other pathologic conditions. However, information about the mechanism of how this therapy works is still very limited.

We postulate that hyperbaric oxygen therapy has an effect on vascular function by modulating mechanisms of vascular responses to various dilator and constrictor agonists in cerebral resistance vessels, leading to restored vascular reactivity. In accordance to this, the therapy affects production of vasodilators and vasoconstrictors, as well as the vessel-sensitivity to these factors.

Furthermore, we hypothesize that hyperbaric oxygen therapy would restore cerebral blood flow regulation that is impaired in diabetics, whereas in contrast to that, chronic intermittent hypoxia would lead to impaired cerebral blood flow. These proposed mechanisms would, if confirmed, represent a valuable advancement in the understanding of this subject.

Pharmacological preconditioning with hyperbaric oxygen: can this therapy attenuate myocardial ischemic reperfusion injury and induce myocardial protection via nitric oxide?
Yogaratnam JZ1, Laden G, Guvendik L, Cowen M, Cale A, Griffin S.
J Surg Res. 2008 Sep;149(1):155-64. Epub 2007 Oct 11.

Ischemic reperfusion injury (IRI) is an inevitable part cardiac surgery such as coronary artery bypass graft (CABG). While ischemic hypoxia and the ensuing normoxic or hyperoxic reperfusion are critical to the initiation and propagation of IRI, conditioning myocardial cells to an oxidative stress prior to IRI may limit the consequences of this injury.

Hyperbaric oxygen (HBO2) is a modality of treatment that is known to generate an oxidative stress. Studies have shown that treatment with HBO2 postischemia and reperfusion is useful in ameliorating myocardial IRI. Moreover, preconditioning the myocardium with HBO2 before reperfusion has demonstrated a myocardial protective effect by limiting the infarct size post ischemia and reperfusion.

Current evidence suggests that HBO2 preconditioning may partly attenuate IRI by stimulating the endogenous production of nitric oxide (NO). As NO has the capacity to reduce neutrophil sequestration, adhesion and associated injury, and improve vascular flow, HBO2 preconditioning induced NO may play a role in providing myocardial protection during interventions that involve an inevitable episode of IRI.

This current opinion review article attempts to suggest that HBO2 may be used to pharmacologically precondition and protect the myocardium from the effects of IRI that is known to occur during cardiac surgery.

Chronic hyperbaric oxygen treatment elicits an anti-oxidant response and attenuates atherosclerosis in apoE knockout mice
Kudchodkar BJ, Pierce A, Dory L.
Atherosclerosis 2007; 193: 28–35.

We previously demonstrated that hyperbaric oxygen (HBO) treatment inhibits diet-induced atherosclerosis in New Zealand White rabbits. In the present study we investigate the mechanisms that might be involved in the athero-protective effect of HBO treatment in a well-accepted model of atherosclerosis, the apoE knockout (KO) mouse. We examine the effects of daily HBO treatment (for 5 and 10 weeks) on the components of the anti-oxidant defense mechanism and the redox state in blood, liver and aortic tissues and compare them to those of untreated apoE KO mice.

HBO treatment results in a significant reduction of aortic cholesterol content and decreased fatty streak formation. These changes are accompanied by a significant reduction of autoantibodies against oxidatively modified LDL and profound changes in the redox state of the liver and aortic tissues.

A 10-week treatment significantly reduces hepatic levels of TBARS and oxidized glutathione, while significantly increases the levels of reduced glutathione, glutathione reductase (GR), transferase, Se-dependent glutathione peroxidase and catalase (CAT).

The effects of HBO treatment are similar in the aortic tissues. These observations provide evidence that HBO treatment has a powerful effect on the redox state of relevant tissues and produces an environment that inhibits oxidation. The anti-oxidant response may be the key to the anti-atherogenic effect of HBO treatment.

Hyperbaric oxygen reduces the progression and accelerates the regression of atherosclerosis in rabbits
Kudchodkar BJ, Wilson J, Lacko A et al.
Arterioscler Thromb Vasc Biol 2000; 20: 1637–1643.


We studied the effect of hyperbaric oxygen (HBO) treatment on the extent of diet-induced accumulation of lipid oxidation products in rabbit plasma and tissues, on plasma paraoxonase activity, and on the extent of progression and regression of atherosclerotic lesions in the rabbit aorta.

HBO treatment of cholesterol-fed rabbits dramatically reduces the development of arterial lesions despite having little or no effect on plasma or individual lipoprotein cholesterol concentrations.
Compared with no treatment in cholesterol-fed animals, HBO treatment also substantially reduces the accumulation of lipid oxidation products (conjugated dienes, trienes, and thiobarbituric acid-reactive substances) in plasma, in the low density lipoprotein and high density lipoprotein fractions of plasma, in the liver, and in the aortic tissues.

In addition, HBO treatment prevents the decrease in plasma paraoxonase activity observed in rabbits fed cholesterol-rich diets. Similarly, in regression studies, HBO treatment has no effect on the rate of plasma (or lipoprotein) cholesterol decline but significantly accelerates aortic lesion regression compared with no treatment.

Direct measures of aortic cholesterol content support these morphological observations. On the basis of these results, we conclude that repeated, but relatively short, exposure to HBO induces an antioxidant defense mechanism(s) that is responsible for retarding the development or accelerating the regression of atherosclerotic lesions.

Clinical studies on various therapy for the intractable trauma of toes and fingers in cases of diabetes mellitus and peripheral ischemic diseases
Kuyama T, Umemura H, Sudo T et al.
Nippon Geka Gakkai Zasshi 1988; 89: 763–770.

In cases of ischemic extremities and diabetes mellitus, the trauma on finger and toe is very intractable. For such injuries amputation of extremity is indicated very often because of severe necrosis. The number of such cases has been increasing recently because many cases of these patients have arteriosclerotic arterial occlusion and diabetes mellitus, and these are correlated with the changes of aging.

The number of cases of Buerger’s disease has been also increasing and it is another etiology of intractable trauma in ischemic extremity. The repeated hyperbaric oxygenation, sympathetic block, warfarin therapy and insulin bath with bubbling of hyperbaric oxygen, were applied to has been of such necrosis. By these procedures, the rate of amputation of extremity decreasing.

It was concluded that the surgical reconstruction of artery for ischemic extremity has never any meaning as the therapy of such intractable injuries, if blood flow in the peripheral tissue is not kept physiologically, before vascular reconstruction. In order to increase peripheral tissue circulation, the hyperbaric oxygenation, sympathetic block and warfarin therapy wer performed in many cases and these methods were very effective for intractable injuries with severe necrosis.

Effect of hyperbaric oxygenation on myocardial blood supply in patients with chronic ischemia of the lower extremities in the preoperative period
Belov KV, Spasskiĭ AA, Levshunov SP, Aliab'ev VS.
Kardiologiia. 1989 Apr;29(4):86-8.

ECG and central hemodynamic parameters were examined in 24 patients with chronic ischemia of lower extremities under the effect of a course of hyperbaric oxygenation, and were shown to be improved in 67% of the cases. Deteriorating ECG pattern in combination with unfavorable central hemodynamic changes, seen in 29%, suggest that electrocardiographic monitoring is essential during the hyperbaric oxygenation course, so that treatment regimen could be timely adjusted.

Results of the conservative treatment of patients with ischemia of the lower extremities by hyperbaric oxygenation
Belov KV, Aliab’ev VS, Shishkin EK.
Vestn Khir Im I I Grek 1987; 139: 43–45.

A comparison is made of results of conservative treatment of 123 patients with ischemia of lower extremities of atherosclerotic genesis. It was shown that the maximum efficiency of the treatment was achieved by an associated application of pharmacological drugs and HBO. An analysis of angiograms has shown that the absence of collaterals is one of the causes of the HBO being inefficient.