The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta.

Abstract

Inducible nitric oxide (NO) produced by macrophages is cytotoxic to invading organisms and has an important role in host defense. Recent studies have demonstrated inducible NO production within the heart, and that cytokine-induced NO mediates alterations in cardiac contractility, but the cytotoxic potential of nitric oxide with respect to the heart has not been defined. To evaluate the role of inducible nitric oxide synthase (iNOS) on cardiac myocyte cytotoxicity, we exposed adult rat cardiac myocytes to either cytokines alone or to activated J774 macrophages in coculture. Increased expression of both iNOS message and protein was seen in J774 macrophages treated with IFNy and LPS and cardiac myocytes treated with TNF-a, EL-1lf, and IFNy. Increased NO synthesis was confirmed in both the coculture and isolated myocyte preparations by increased nitrite production. Increased NO synthesis was associated with a parallel increase in myocyte death as measured by CPK release into the culture medium as well as by loss of membrane integrity, visualized by trypan blue staining. Addition of the competitive NO synthase inhibitor L-NMMA to the culture medium prevented both the increased nitrite production and the cytotoxicity observed after cytokine treatment in both the isolated myocyte and the coculture experiments. Because transforming growth-factor beta modulates iNOS expression in other cell types, we evaluated its effects on cardiac myocyte iNOS expression and NO-mediated myocyte cytotoxicity.TGF-fi reduced expression of cardiac myocyte iNOS message and protein, reduced nitrite production, and reduced NO-mediated cytotoxicity in parallel. Taken together, these experiments show the cytotoxic potential of endogenous NO production within the heart, and suggest a role for TGF-fi or NO synthase antagonists to mute these lethal effects.

Short-Term Statin Therapy Improves Cardiac Function and Symptoms in Patients With Idiopathic Dilated Cardiomyopathy

“…14,15 These cytokines, especially TNF-␣ and IL-6, exert negative inotropic effects and induce apoptosis in cardiac myocytes. 16 Although the anti-inflammatory effects of statins may contribute to some of their beneficial effects in CHF, we cannot exclude the possibility that plasma levels of TNF-␣ and IL-6 were reduced in response to improvement in cardiac function by statins.…”

Cytokine Gene Expression During the Development of Graft Coronary Artery Disease in Mice

“…49,50 Macrophages are potent effector cells in allograft rejection and can release effector molecules such as nitric oxide and TNF-. [51][52][53][54] In addition to these direct effector molecules, other immune mediators such as IL-10 and IL-6 55 are also produced by activated macrophages. IL-10 production by macrophages by itself could have anti-inflammatory effects in allograft rejection in an autocrine or paracrine manner, because it can inhibit inflammatory cytokine production, 56 MHC II expression, 57 and costimulatory molecule expression 58 by monocytes/macrophages.…”

Enhancement of the haemodynamic effects of NG‐monomethyl‐l‐arginine by transforming growth factor‐β1 in conscious, normal, but not endotoxaemic, rats

“…In this context, it is notable that TGF-f, has been shown to protect against myocardial and endothelial injury caused by ischaemia and reperfusion (Lefer et al, 1990;, possibly through influencing processes mediated by tumour necrosis factor, or nitric oxide (NO; Lefer et al, 1990;. Indeed, it has been found that TGF-0, inhibits cytoline-induced NO production by macrophages (Ding et al, 1990), human and rat aortic smooth muscle cells Schini et al, 1992), and rat ventricular myocytes (Pinsky et al, 1995). Furthermore, TGF-l, also down-regulates inducible NOS (iNOS) mRNA in rat aortic smooth muscle cells (Perrella et al, 1994).…”