Key result
TNF-alpha and LPS increase macrophage iNOS expression ~365% but fail to induce it in cardiac myocytes.
Why the study?
Proinflammatory cytokines including TNF-alpha are elevated in cardiac conditions and linked to cardiac dysfunction, but the differential effect of TNF-alpha on iNOS expression in macrophages versus cardiac myocytes is unclear.
p-value: p=< 0.01
HL-1 cardiac myocyte iNOS cannot be induced by TNF-alpha alone, unlike macrophage iNOS, suggesting diverse regulatory pathways for cardiac dysfunction secondary to proinflammatory cytokines.
Hypothesis-generating for cell-specific iNOS regulation; requires validation in intact models before clinical translation.
Proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), are elevated during cardiopulmonary bypass (CPB), heart failure, and inflammatory cardiac and systemic diseases. Elevated TNF-alpha has been linked to diminished cardiac function, decreased systemic vascular resistance, as well as renal and pulmonary dysfunction. It is understood that myocardial tissues can express TNF-alpha, which results in the induction of inducible nitric oxide synthase (iNOS) leading to a significant decline in cardiac function and other direct effects. The hypothesis of this study was to determine if TNF-alpha would stimulate iNOS and its product nitric oxide (NO) similarly in immortalized macrophage and cardiac myocytes. Cultured macrophages (RAW 264.7) and cardiac myocytes (HL-1) were placed into two treatment groups and a control. The treatments included: (1) TNF-alpha and lipopolysaccharide (LPS); and (2) LPS, TNF-alpha, interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) incubated for 8 h. The macrophage expression of iNOS increased by 365% (p < 0.01) and its product, NO, increased proportionally. The expression of iNOS in the cardiac myocyte did not increase with TNF-alpha and LPS. However, with the addition of IFN-alpha and IL-1beta iNOS increased to 140% of control (p < 0.05). Myocyte cGMP and NO did not increase significantly with TNF-alpha treatment. This study suggests that HL-1 myocyte iNOS cannot be induced by TNF-alpha, unlike macrophage iNOS. Furthermore, the resultant cardiac dysfunction, secondary to proinflammatory cytokines effects, is regulated via diverse pathways.
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Sanders et al. (2001) studied this question. TNF-alpha and LPS vs. control was evaluated on expression of iNOS (p=< 0.01). TNF-alpha and LPS increased iNOS expression by 365% in macrophages (p<0.01) but did not induce iNOS in cardiac myocytes, which required additional cytokines to reach 140% of control (p<0.05).
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