Roles of insulin-like growth factor II in cardiomyoblast apoptosis and in hypertensive rat heart with abdominal aorta ligation.

Abstract

Although IGF-II activating the IGF-II receptor signaling pathway has been found to stimulate cardiomyocyte hypertrophy, the role of IGF-II in cardiac cell apoptosis remains unclear. This study aimed to identify the roles of IGF-II and/or IGF-II receptors (IGF-II/IIR) in cardiomyoblast apoptosis and in hypertensive rat hearts with abdominal aorta ligation. Cultured rat heart-derived H9c2 cardiomyoblasts and excised hearts from Sprague-Dawley rats with 0- to 20-day complete abdominal aorta ligation, a model of ANG II elevation and hypertension, were used. IGF-II/IIR expression, caspase activity, DNA fragmentation, and apoptotic cells were measured by RT-PCR, Western blot, agarose gel electrophoresis, and TUNEL assay following various combinations of ANG II, IGF-II/IIR antibody, CsA (calcineurin inhibitor), SP-600125 (JNK inhibitor), SB-203580 (p38 inhibitor), U-0126 (MEK inhibitor), or Staurosporine (PKC inhibitor) in H9c2 cells. ANG II-induced DNA fragmentation and TUNEL-positive cells were blocked by IGF-II/IIR antibodies and antisense IGF-II, but not by IGF-II sense. IGF-II-induced apoptosis was blocked by IGF-IIR antibody and CsA. The increased gene expressions of IGF-II and -IIR induced by ANG II were reversed by U-0126 and Sp600125, respectively. Caspase 8 activities induced by ANG II were attenuated by U-0126, SP-600125, and CsA. DNA fragmentation induced by ANG II was totally blocked by SP-600125, and CsA and was attenuated by U-0126. In rats with 0- to 20-day complete abdominal aorta ligation, the increases in IGF-II/IIR levels in the left ventricle were accompanied by hypertension as well as increases in caspase 9 activities and TUNEL-positive cardiac myocytes. ANG II-induced apoptosis was reversed by IGF-II/IIR blockade and coexisted with increased transactivation of IGF-II and -IIR, which are mediated by ERK and JNK pathways, respectively, both of which further contributed to cardiomyoblast apoptosis via calcineurin signaling. The increased cardiac IGF-II, IGF-IIR, caspase 9, and cellular apoptosis were also found in hypertensive rats with abdominal aorta ligation.

• Authors: Shin-Da Lee, Chun-Hsien Chu, Erh-Jung Huang, Min-Chi Lu, Jer-Yuh Liu, Chung-Jung Liu, Hsi-Hsien Hsu, James A Lin, Wei-Wen Kuo, Chih-Yang Huang
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 291 Issue 2 Pg. E306-14 (Aug 2006) ISSN: 0193-1849 [Print] United States
• PMID: 16825605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensins
• Receptor, IGF Type 2
• Insulin-Like Growth Factor II

Topics

• Angiotensins (pharmacology)
• Animals
• Aorta, Abdominal (surgery)
• Apoptosis
• Cell Line
• Dose-Response Relationship, Drug
• Hypertension (metabolism)
• Insulin-Like Growth Factor II (metabolism)
• Ligation
• Male
• Muscle Cells (drug effects, metabolism, pathology)
• Myocardium (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, IGF Type 2 (metabolism)