Akt signaling as a mediator of cardiac adaptation to low birth weight

Abstract

Intrauterine insults, such as poor nutrition and placental insufficiency, can alter cardiomyocyte development, and this can have significant long-term implications for heart health. Consequently, epidemiological studies have shown that low-birth-weight babies have an increased risk of death from cardiovascular disease in adult life. In addition, intrauterine growth restriction can result in increased left ventricular hypertrophy, which is the strongest predictor for poor health outcomes in cardiac patients. The mechanisms responsible for these associations are not clear, but a suboptimal intrauterine environment can program alternative expression of genes such as cardiac IGF-2/H19, IGF-2R and ATR through either an increase or decrease in DNA methylation or histone acetylation at specific loci. Furthermore, hypoxia and other intrauterine insults can also activate the IGF-1 receptor via IGF-1 and IGF-2, and the AT receptor via angiotensin signaling pathways; both of which can result in the phosphorylation of Akt and the activation of a range of downstream pathways. In turn, Akt activation can increase cardiac angiogenesis and cardiomyocyte apoptosis and promote a reversion of metabolism in postnatal life to a fetal phenotype, which involves increased reliance on glucose. Cardiac Akt can also be indirectly regulated by microRNAs and conversely can target microRNAs that will eventually affect other specific cardiac genes and proteins. This review aims to discuss our understanding of this complex network of interactions, which may help explain the link between low birth weight and the increased risk of cardiovascular disease in adult life.

Subcutaneous maternal resveratrol treatment increases uterine artery blood flow in the pregnant ewe and increases fetal but not cardiac growth

“…Interestingly, we found that maternal RSV supplementation increased the mRNA expression of IGF1 and decreased the expression of IGF2R. These signalling molecules are involved in physiological and pathological cardiac growth, respectively Wang et al 2012aWang et al , 2017. Although IGF1 mRNA expression was increased in the RSV-treated group, there was no evidence that downstream AKT/mTOR signalling was increased.…”

“…; Wang et al . , ). Although IGF1 mRNA expression was increased in the RSV‐treated group, there was no evidence that downstream AKT/mTOR signalling was increased.…”

MicroRNA-18a inhibits cell growth and induces apoptosis in osteosarcoma by targeting MED27

“…miR-18a is a member of the miR-17-92 family cluster, which includes 6 individual miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b1 and miR-92a1, which are amplified in lymphomas and other cancer cells (13)(14)(15). This cluster and its paralogues play important roles in cancer development due to their ability to suppress the expression of a number of tumor-associated proteins, such as p53 and Akt (13)(14)(15), the overexpression of which promotes cell viability and reduces apoptosis by regulating cell cycle progression (16)(17)(18)(19). The miR-17-92 cluster also plays an important role in normal growth and skeletal development.…”

IUGR decreases cardiomyocyte endowment and alters cardiac metabolism in a sex- and cause-of-IUGR-specific manner

“…IUGR lambs of pregnancies with placental restriction have increased cardiac phosphorylation of the insulin receptor, increased glucose transporter-1 (GLUT-1), and increased pyruvate dehydrogenase kinase-4 compared with controls at 21 days of age (81,82), which suggests greater glycolysis. Interestingly, this altered metabolism is coupled with greater left ventricle (LV) weight relative to body weight (LV hypertrophy; LVH) compared with controls (83).…”