(Circulation. 1995;91:1520-1524.)
© 1995 American Heart Association, Inc.
Articles |
Hypoxic Stress Induces Cardiac Myocyte–Derived Interleukin-6
From the Department of Medicine III, Osaka University Medical School, Suita, Osaka, Japan.
Correspondence to Keiko Yamauchi-Takihara, MD, PhD, Department of Medicine III, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan.
Background Hypoxic and ischemic stresses cause a series of
well-documented changes in myocardial cells and tissues, including loss
of contractility, changes in lipid and fatty acid metabolism, and
irreversible membrane damage leading to eventual cellular death.
Activated neutrophils are considered to be involved in this myocardial
cellular injury. By stimulation of the neutrophils with chemotactic
factors, canine neutrophils can be induced to adhere to isolated
cardiac myocytes only if the myocytes have been previously exposed to
cytokines such as tumor necrosis factor–
, interleukin (IL)-1, and
IL-6.
Methods and Results To examine the possible involvement of IL-6 in ischemia-reperfusion injury, we used cultured rat neonatal cardiac myocytes to study the effects of hypoxic stress on the production of IL-6 by cardiac myocytes. Unstimulated cardiac myocytes (3x105 cells per dish) produced 320 pg IL-6 over 4 hours in vitro (ie, biological activity equal to 320 pg recombinant IL-6, as detected by bioassay using the MH-60.BSF2 cell line). The incubation of cardiac myocytes under hypoxic conditions for 4 hours induced significantly increased production of IL-6 compared with normoxic conditions (2.82±0.49 versus 1.64±0.18 U/mL, P<.05). Furthermore, reoxygenation for 2 hours after 2 hours of hypoxic stress significantly augmented the production of IL-6 by cardiac myocytes (4.34±0.52 U/mL, P<.05). These responses to hypoxia and reoxygenation were not observed in fibroblasts isolated from the same tissue. Although unstimulated cardiac myocytes lacked IL-6 mRNA expression detectable by Northern blot analysis, hypoxic stress induced the expression of IL-6 mRNA in the cardiac myocytes. Several pathophysiologically relevant factors also augmented IL-6 release from cultured cardiac myocytes, including IL-1ß, ionomycin, and epinephrine.
Conclusions Cardiac myocytes respond to hypoxic stress to augment the production of IL-6, and the IL-6 derived from cardiac myocytes may play an important role in the progression of myocardial dysfunction observed in cardiac ischemia-reperfusion injury.
Key Words: ischemia • heart diseases • reperfusion injury
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