The Effects of Prenatal Protein Restriction onβ-Adrenergic Signalling of the Adult Rat Heart during Ischaemia Reperfusion

Abstract

A maternal low-protein diet (MLP) fed during pregnancy leads to hypertension in adult rat offspring. Hypertension is a major risk factor for ischaemic heart disease. This study examined the capacity of hearts from MLP-exposed offspring to recover from myocardial ischaemia-reperfusion (IR) and related this to cardiac expression of β-adrenergic receptors (β-AR) and their associated G proteins. Pregnant rats were fed control (CON) or MLP diets (n = 12 each group) throughout pregnancy. When aged 6 months, hearts from offspring underwent Langendorff cannulation to assess contractile function during baseline perfusion, 30 min ischemia and 60 min reperfusion. CON male hearts demonstrated impaired recovery in left ventricular pressure (LVP) and dP/dt max (P < 0.01) during reperfusion when compared to MLP male hearts. Maternal diet had no effect on female hearts to recover from IR. MLP males exhibited greater membrane expression of β 2-AR following reperfusion and urinary excretion of noradrenaline and dopamine was lower in MLP and CON female rats versus CON males. In conclusion, the improved cardiac recovery in MLP male offspring following IR was attributed to greater membrane expression of β 2-AR and reduced noradrenaline and dopamine levels. In contrast, females exhibiting both decreased membrane expression of β 2-AR and catecholamine levels were protected from IR injury.

Mechanisms involved in developmental programming of hypertension and renal diseases. Gender differences

“…This sex-specific effect is consistent with findings in rats in which IUGR, as a result of either hypoxia or low protein diet, caused cardiac remodeling and impaired recovery to ischemia-reperfusion in adult male offspring, but had no effect on the female heart [47]. It has also been shown that female rats exposed to chronic prenatal hypoxia exhibited an improved contractility and increased coronary flow with respect to male rats [48,56]. Moreover, human studies showed that IUGR children tend to keep their relatively smaller left cardiac structures in adulthood.…”

Ischemia/Reperfusion

“…In addition, recent work indicates that prenatal exposure to hypoxia or cocaine inhibit the infarct-sparing effects of ischemic preconditioning later in adult life by a mechanism involving irreversible fetal reprogramming of protein kinase C epsilon expression (561, 626). A large number of studies have provided evidence that adult animals that were exposed to hypoxia, glucocorticoids or maternal low protein diet or obesity in fetal life demonstrate an increased susceptibility to I/R in the early postnatal period (108a, 211a, 211b, 268a, 268b, 327a, 390a, 491a, 491b, 626, 626a, 626b, 660, 675b, 676a, 782, 863a, 864a, 864b, 864c). These results support the notion that a fetus developing in adverse conditions becomes an adult who is susceptible to enhanced I/R injury.…”

“…With regard to adult susceptibility to I/R after fetal stress, there is a growing body of evidence indicating that reductions in the expression of cardioprotective genes such as protein kinase Cε (PKCε), endothelial nitric oxide synthase (eNOS), adenosine monophosphate (AMP) kinase, and heat-shock protein70 by a ROS-mediated, but nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-independent epigenetic repression mechanism may play a role (211a, 268b, 390a, 491a, 491b, 626, 626a, 626b, 864a). In addition, fetal hypoxia induces changes in extracellular matrix and myofibrillar architecture, oxidative stress, diastolic dysfunction, reduced capillary density, sympathetic dominance, glucocorticoid receptor deficiency, and altered endothelium-dependent vasodilator function in adult hearts, which may contribute to this enhanced susceptibility to I/R (108a, 211b, 268a, 268b, 327a, 327b, 675a, 675b, 675c, 675d, 676a, 857, 863a). …”

Exposure of neonatal rats to maternal cafeteria feeding during suckling alters hepatic gene expression and DNA methylation in the insulin signalling pathway

“…Protein expression was determined using Western blot, as described previously (Ryan et al 2012). Primary antibodies were PPARa (Cayman Chemicals), PPARg (Santa Cruz), Glut2 (Millipore) and insulin receptor beta (cell signalling).…”