Celastrol: A New Therapeutic Potential of Traditional Chinese Medicine

I nflammation and oxidative stress play a pivotal role in the development of atherosclerosis, and they are strongly associated with cardiovascular disease risk, including hypertension and metabolic syndrome. Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme that catalyzes heme into equimolar amounts of carbon monoxide, biliverdin/bilirubin, and the release of free iron. In recent years, HO-1 expression has been shown to have an important protective endogenous mechanism, especially against oxidative and inflammatory insults. A number of animal studies have revealed that induction of HO-1 in various tissues has shown beneficial effects in several pathological conditions, such as myocardial infarction, ischemia-reperfusion systems, or atherosclerosis.1 Celastrol is a quinone methide triterpenoid isolated from the traditional Chinese medicine “Thunder of God Vine” (Tripterygium wilfordii Hook F.) that has been used to treat autoimmune diseases, chronic inflammation, neurodegenerative diseases, and many types of cancer.2 Studies to define its pharmacological mechanisms revealed that it suppresses many steps to induce inflammation or oxidative stress, including heat-shock protein 90 and nuclear factor-κB signaling pathway.3 In this issue of the American Journal of Hypertension, Yu et al. report their studies to investigate the potential beneficial effects of celastrol on cardiovascular system under hypertensive status both in vivo and in vitro.4 The results reveal that celastrol lowered blood pressure and enhanced insulin sensitivity, respectively, with improved cardiac and vascular hypertrophy in rats with hypertension induced by fructose feeding. Celastrol also reduced hypertension-elicited increases in production of inflammatory cytokines as well as reactive oxygen species through inhibition of ERK1/2 and Akt phosphorylation. Interestingly, hydralazine failed to ameliorate such pathophysiological changes, although it normalized blood pressure to levels similar to that of celastrol, suggesting that the beneficial effects of celastrol on the cardiovascular system are independent of blood pressure reduction. More importantly, the Yu studies clearly demonstrate that celastrol stimulated HO-1 expression and activity, whereas an inhibitor of HO-1, zinc protoporphyrin, significantly abolished the beneficial effects of celastrol on hypertension-induced cardio vascular changes. From these observations, the authors concluded that celastrol attenuates hypertension-induced inflammation and oxidative stress in cardiovascular system via HO-1 induction and that it can be used as a novel medication in the therapy of hypertension. Natural products that induce HO-1 have been proposed as potential new drugs for the treatment of diseases in which inflammation or oxidative stress is involved.5 Upregulation of the HO-1, however, may not be always beneficial for cells: heme depletion, and accumulation of CO and bilirubin are potentially toxic.6 Therefore, pharmacological modulators of HO-1 activity should act to achieve desired therapeutic effects without any adverse effects. Achieving this may be more difficult than it seems because adverse effects have to be defined in terms of each of the enzymatic products of heme metabolism by HO-1. Furthermore, sensitivity to the therapeutic or adverse effects of these products is likely to be tissue specific. Novel drug-delivery systems may be needed to provide the appropriate dose of the HO-1 modulator to selected tissue targets to exert its pharmacological effects safely. Celastrol may need to pass such hurdles before entering the armory of antihypertensive drugs.