Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia

Abstract

Intrauterine hypoxia is a common complication during pregnancy and could increase the risk of cardiovascular disease in offspring. However, the underlying mechanism is controversial. Memantine, an NMDA receptor antagonist, is reported to be a potential cardio-protective agent. We hypothesized that antenatal memantine treatment could prevent heart injury in neonatal offspring exposed to intrauterine hypoxia. Pregnant rats were exposed to gestational hypoxia or antenatal memantine treatment during late pregnancy. Newborns were then sacrificed to assess multiple parameters. The results revealed that Intrauterine hypoxia resulted in declining birth weight, heart weight, and an abnormally high heart weight/birth weight ratio. Furthermore, intrauterine hypoxia caused mitochondrial structural, functional abnormalities and decreased expression of DRP1, and upregulation of NMDAR1 in vivo. Antenatal memantine treatment,an NMDARs antagonist, improved these changes. In vitro, hypoxia increased the glutamate concentration and expression of NMDAR1. NMDAR activation may lead to similar changes in mitochondrial function, structure, and downregulation of DRP1 in vitro. Pharmacological blockade of NMDARs by the non-competitive NMDA antagonist MK-801 or knockdown of the glutamate receptor NR1 significantly attenuated the increased mitochondrial reactive oxygen species and calcium overload-induced by hypoxia exposure. These facts suggest that memantine could provide a novel and promising treatment for clinical use in intrauterine hypoxia during pregnancy to protect the cardiac mitochondrial function in the offspring. To our best knowledge, our research is the first study that shows intrauterine hypoxia can excessively activate cardiac NMDARs and thus cause mitochondrial dysfunction.

The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

“…Finally, NMDA-induced myocardial fibrosis, which may predispose ventricles to arrhythmias [ 57 ], can also by triggered by intracellular Ca 2+ overload. In accord, many reports have demonstrated that NMDAR stimulation can induce mitochondrial depolarization, reactive oxygen species (ROS) production, and caspase-3-mediated apoptosis in rat ventricular cardiomyocytes ( Figure 3 A) [ 46 , 47 ]. Similarly, NMDARs promoted Ca 2+ influx and Ca 2+ -dependent apoptosis by enhancing p38 MAPK activity in primary human neonatal cardiomyocytes cultured under ischemic conditions [ 65 ].…”

Exploring the Association between Oxygen Concentration and Life Expectancy in China: A Quantitative Analysis

“…Similarly, several studies had shown that hypoxia was closely related to the pathogenesis of CKD [42,43], stroke [14,44], cirrhosis, and other CLD [39]. During pregnancy, the mother or the baby is exposed to a hypoxic environment, which may affect the normal development of the child's brain [45,46], heart [47], or other organs [48], increasing the risk for the development of neonatal diseases [46]. Interestingly, our results showed that the age-standardized YLLs per 100,000 population of tracheal, bronchus, and lung cancers were significantly lower in the cluster of provinces with lower oxygen concentration (see Table 3), which seemed to conflict with the findings that hypoxia may have a general negative impact on the pulmonary system.…”

Antioxidant Hydrogels: Antioxidant Mechanisms, Design Strategies, and Applications in the Treatment of Oxidative Stress‐Related Diseases

“…In the presence of oxidative stress, there is an elevation in mitochondrial ROS production, potentially resulting in oxidative impairment of the mitochondrial membrane. [ 42 ] This in turn influences energy generation and cellular functionality. The mitochondrial antioxidant enzyme system is a pivotal mechanism for shielding mitochondria against the harm induced by oxidative stress.…”