Leptin, endothelin, NADPH oxidase, and heart failure.

Leptin, Endothelin, NADPH Oxidase, and Heart Failure To the Editor: We read with great interest the article by Dong et al1 in the February 2006 issue of Hypertension. They showed that leptin suppresses cardiac contractile function in ventricular myocytes by an endothelin-1 and NADPH oxidase–dependent pathway. Interestingly, both endothelin receptor A and B antagonists were able to attenuate the cardiac functional abnormalities in response to leptin. In human myocardium, mainly the endothelin receptor A is functionally important and upregulated by heart failure.2 Furthermore, we found that patients with New York Heart Association stage III have, even independent of body mass index, higher leptin levels than New York Heart Association II patients and normal subjects.3 The impaired contractility in response to leptin observed by Dong et al1 in vitro could also play a role in the decreased ventricular function of obese patients with heart failure. We found an induction of NADPH oxidase subunit expression and superoxide anion formation by endothelin-1 in human endothelial cells.4 Furthermore, transgenic endotheliumrestricted overexpression of human endothelin-1 caused increased oxidative stress, augmented activity and expression of vascular NADPH oxidase, vascular remodeling, and endothelial dysfunction.5 Therefore, augmented endothelin levels observed in obese patients could increase superoxide anion formation in the vascularized myocardial tissue in vivo by an additional mechanism and could further potentiate the suppressive effect on cardiac contractile function. Dong et al1 analyzed the subunit expression of the classical NADPH oxidase complex. Recently, several additional NADPH oxidase complexes have been discovered. Some of these novel NADPH oxidase complexes are involved in development and progression of cardiovascular diseases.6 Unpublished data from our laboratory suggest, in addition to the classical gp91/Nox2 complex, the expression of Nox1and Nox4-containing NADPH oxidase complexes in isolated cardiomyocytes. Therefore, the leptin-mediated effects on contractile function might involve additional novel NADPH oxidase complexes as well. In conclusion, growing evidence supports a role of the obese gene product leptin in the activation of an endothelin-1 and NADPH oxidase-dependent pathway leading to impaired endothelial and cardiac function. These data suggest a link between obesity, hypertension, oxidative stress, and heart failure.