IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb.
Kimberley C W WangDarran N ToshSong ZhangI Caroline McMillenJaime A DuffieldDoug A BrooksJanna L MorrisonPublished in: American journal of physiology. Regulatory, integrative and comparative physiology (2015)
The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.
Keyphrases
- binding protein
- pi k akt
- left ventricular
- low birth weight
- growth hormone
- signaling pathway
- gene expression
- dna methylation
- preterm infants
- cardiovascular disease
- preterm birth
- type diabetes
- human milk
- birth weight
- cell proliferation
- heart failure
- transcription factor
- mitral valve
- acute myocardial infarction
- body mass index
- metabolic syndrome
- pulmonary hypertension
- histone deacetylase
- epithelial mesenchymal transition
- aortic valve
- acute coronary syndrome
- weight gain
- angiotensin ii
- mass spectrometry
- cardiac resynchronization therapy
- high resolution
- percutaneous coronary intervention
- congenital heart disease