Identifying Disease Pathogenesis and Novel Therapeutic Targets in Cardiovascular Disease
Open Access DepositedCardiovascular disease is the leading cause of death worldwide, with over 695,000 deaths annually. In this dissertation, we first investigate the fetal basis of adult cardiac disease susceptibility, a hypothesis that adult, cardiometabolic disease can originate from childhood insults that modify epigenetic markers. To mimic pediatric hypoxia exposure, we exposed neonatal rats to chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea, for four weeks from birth to understand hypoxia-induced transcriptomic responses. While we did not observe overt functional cardiac deficits after one month of CIH, our results demonstrated sex-dependent differentially expressed genes and dysregulated miRNAs. Ongoing research will determine if these transcriptomic alterations during the critical growth period manifest into physiologic, metabolic, and cardiac consequences in adulthood. Next, in ovariectomized rats, we investigated aging-related diseases induced by high fat diet and CIH exposure. We examined the link between hypoxia exposure and cognitive decline in ovariectomized rats and demonstrated that hypoxia correlates with spatial learning deficits and subsequent memory impairment. This cognitive decline was associated with upregulated total tau in the hippocampus, a biomarker of Alzheimer’s disease. We further hypothesized that aging, obesity, and CIH in females would induce cardiac dysfunction that mimics diastolic dysfunction associated with heart failure with preserved ejection fraction (HFpEF). In this animal model, we tested whether hypothalamic paraventricular oxytocin (PVN OXT) neuron activation would prevent the development of diastolic dysfunction. PVN OXT neuron activation provides excitatory neurotransmission to cardiac vagal neurons, which increases parasympathetic input to the heart, and this treatment has previously demonstrated efficacy in models of myocardial infarction, cardiac pressure overload, and hypertension. Our in vivo results demonstrate that CIH exposure promoted diastolic dysfunction, and treatment with PVN OXT neuron activation alleviated diastolic dysfunction, reduced cardiac fibrosis, and prevented calcium handling changes associated with heightened sympathetic activity. Overall, this treatment paradigm demonstrated efficacy in preventing diastolic dysfunction. Future work will study whether systemic delivery of oxytocin will also provide cardio-protection in the setting of obesity, CIH, and aging in female and male rats.
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