Effects of a postnatal high-salt diet on cardiovascular outcomes in offspring from hypoxic pregnancies

Abstract

Abstract Prenatal hypoxia is a common complication in pregnancy that can alter fetal cardiac development and increase cardiovascular risk later in life. In addition, a poor postnatal diet is thought to exacerbate these effects, but the mechanisms remain largely unknown. This thesis aimed to investigate how exposure to prenatal hypoxia, with or without a postnatal high-salt diet, affects adult cardiac function and associated changes in calcium cycling and metabolic proteins in Wistar rat offspring. Pregnant Wistar rats were exposed to either normoxia (21% O₂) or hypoxia (10.5% O₂) from gestational days 15–20. Male offspring were fed either a normal-salt diet (0.3% NaCl) or a high-salt diet (8% NaCl) from 5 weeks of age until adulthood. Cardiovascular function was assessed using echocardiography and blood pressure with the tail-cuff method. Hearts were collected for histology, calcium-handling protein analysis, and mitochondrial enzyme assays in the left and right ventricles. Prenatal hypoxia alone produced a clear right-ventricular phenotype. Offspring displayed signs of pulmonary hypertension and right-ventricular thickening, together with reduced mitochondrial content and lower Complex V activity in the right ventricle. In contrast, the left ventricle showed an adaptive pattern, with increased citrate synthase activity and selective changes in Complex I and II, while overall structure and function were preserved. However, calcium-handling protein expression remained unchanged in both ventricles. Postnatal exposure to a high-salt diet in normoxic offspring induced a different set of changes. High salt-fed animals developed systemic hypertension, left-ventricular wall thickening, and impaired relaxation. In addition, high salt increased Complex I activity and tended to reduce Complex II activity in the right ventricle. Also phosphorylated RyR2 was reduced in the right ventricle of high-salt animals, suggesting altered calcium release regulation. Structural and calcium-handling protein expression remained relatively stable. When prenatal hypoxia and high salt occurred together, the adult phenotype reflected features of both exposures with no interaction. Interestingly, the combination blunted the hypoxia-induced increase in citrate synthase in the left ventricle, but did not produce major synergistic effects on structure or function. Nevertheless, the metabolic alterations indicated increased ventricular vulnerability to prenatal hypoxia, particularly in the right ventricle. A related study included in this thesis showed that prenatal hypoxia also alters the electrophysiological properties of the heart, thereby increasing arrhythmic susceptibility in adult offspring. This supports the broader concept that the hypoxic intrauterine environment programs multiple aspects of cardiac vulnerability. Overall, the data presented in this thesis show that prenatal hypoxia and a postnatal high salt diet each impose distinct cardiac stresses in adulthood, with more pronounced effects on mitochondrial function. In addition, the findings suggest that these alterations may reflect an early compensatory phase that delays the onset of overt dysfunction. More pronounced interactions may become apparent later in life.