Abstract
gp130, a common receptor for the interleukin 6 family, plays pivotal roles in growth and survival of cardiac myocytes. In the present study, we examined the role of gp130 in pressure overload-induced cardiac hypertrophy using transgenic (TG) mice, which express a dominant negative mutant of gp130 in the heart under the control of alpha myosin heavy chain promoter. TG mice were apparently healthy and fertile. There were no differences in body weight and heart weight between TG mice and littermate wild type (WT) mice. Pressure overload-induced increases in the heart weight/body weight ratio, ventricular wall thickness, and cross-sectional areas of cardiac myocytes were significantly smaller in TG mice than in WT mice. Northern blot analysis revealed that pressure overload-induced up-regulation of brain natriuretic factor gene and down-regulation of sarcoplasmic reticulum Ca(2+) ATPase 2 gene were attenuated in TG mice. Pressure overload activated ERKs and STAT3 in the heart of WT mice, whereas pressure overload-induced activation of STAT3, but not of ERKs, was suppressed in TG mice. These results suggest that gp130 plays a critical role in pressure overload-induced cardiac hypertrophy possibly through the STAT3 pathway.
Highlights
Because recent clinical studies have suggested that cardiac hypertrophy is an independent risk factor of cardiac morbidity and mortality [1], it has become even more important to clarify the mechanism of how cardiac hypertrophy is developed
Pressure overload activated Extracellular Signal-regulated Kinases (ERKs) and STAT3 in the heart of wild type (WT) mice, whereas pressure overload-induced activation of STAT3, but not of ERKs, was suppressed in TG mice. These results suggest that gp130 plays a critical role in pressure overload-induced cardiac hypertrophy possibly through the STAT3 pathway
Cardiac Hypertrophy Induced by Pressure Overload—Constriction of the abdominal aorta is an established method to produce pressure overload-induced cardiac hypertrophy [21, 22]. 4 weeks after the operation, all mice were healthy, and the blood pressure monitored at right carotid artery was elevated as reported before in our laboratory [22] without any differences between TG mice and WT mice
Summary
Because recent clinical studies have suggested that cardiac hypertrophy is an independent risk factor of cardiac morbidity and mortality [1], it has become even more important to clarify the mechanism of how cardiac hypertrophy is developed. Cardiomyocyte hypertrophy can be induced by a variety of factors such as mechanical stress [2], cathecholamines [3], angiotensin II [4], endothelin-1 [5], and cytokines [6]. Hemodynamic overload, namely mechanical stress, is clinically most important. We and others [7,8,9] have reported that mechanical stress induces cardiomyocyte hypertrophy through vasoactive peptides such as angiotensin II and endothelin-1. To determine the physiological significance of gp130 in load-induced cardiac hypertrophy, we generated transgenic (TG) mice, which express a dominant negative form of gp130 in the heart and examined hypertrophic responses by pressure overload produced by constriction of the abdominal aorta
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