Impaired IGF-I signalling of hypertrophic hearts in the developmental phase of hypertension in genetically hypertensive rats.
Insulin-like growth factor-I (IGF-I) signalling is reported to contribute to the modulation of blood pressure and set survival and hypertrophic responses in cardiac tissue. However, whether IGF-I signalling normally acts in cardiac tissues of hypertensive rats is unknown. In this study, using spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SPSHR), both with early blood pressure increases, and Wistar-Kyoto (WKY) rats as controls, we measured the hypertrophic and IGF-I signalling activity changes in rat hearts at 4, 6 and 12 weeks of age. Both SHR and SPSHR were found to have significantly increased blood pressures and ratios of heart- and left ventricle- to body weight at 12 weeks of age. However, IGF-IR and its downstream signalling, including the protein levels of PI3K and phosphorylated Akt, known to maintain physiological cardiac hypertrophy and cardiomyocyte survival, were downregulated. The results of dot blotting showed that cardiac mRNA levels of IGF-I in hypertensive rats were higher than those in controls starting from the age of 4 weeks. This difference suggests the increased ligand IGF-I mRNA levels may be a compensatory response caused by the impaired IGF-I signalling. Moreover, enhanced cardiac cytosolic cytochrome-c, a mitochondria-dependent apoptotic pathway component, tended to occur in both hypertensive rats, although it did not reach a significant level. These findings indicate that impaired IGF-IR signalling occurs at early stages, and it may contribute, at least partially, to the development of hypertension and pathological cardiac hypertrophy and to cardiomyocyte apoptosis at later stages in SHR and SPSHR.
Kuo
Wei-Wen
WW
Institute of Biochemistry, Chung-Shan Medical University, Taichung, Taiwan.
Chu
Chia-Yih
CY
Wu
Chieh-Hsi
CH
Lin
James A
JA
Liu
Jer-Yuh
JY
Hsieh
Yi-Hsien
YH
Ueng
Kwo-Chang
KC
Lee
Shin-Da
SD
Hsieh
Dennis Jine-Yuan
DJ
Hsu
His-Hsien
HH
Chen
Li-Mien
LM
Huang
Chih-Yang
CY
D000375:Aging; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology*; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006352:Heart Ventricles / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction
D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D045304:Cytochromes c