Outcomes and Mechanisms of Cardioprotection Motivated by Selective Parasympathetic Activation
Open AccessDespite numerous surgical and pharmaceutical interventions, cardiovascular diseases remain the leading global cause of death, underscoring the need for new treatments. A hallmark of cardiovascular disease is autonomic imbalance characterized by an overactivation in sympathetic drive, and a withdrawal of parasympathetic tone. Some common pharmaceutical therapies function by dampening this sympathetic overactivation; however, this does not address the concomitant reduction in parasympathetic activity to the heart. Restoring cardiac parasympathetic activity to the diseased heart has emerged as an exciting alternative to current treatments. Recent work has identified a group of oxytocin neurons (OXT) in the paraventricular nucleus of the hypothalamus (PVN) that provide powerful excitation to cardiac vagal neurons in the brainstem, resulting in increased parasympathetic activity to the heart. In vivo studies showed reduced mean arterial pressure and heart rate (HR) via selective activation of PVN OXT neurons using chemogenetic expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This dissertation aims to characterize the effect of increasing parasympathetic activity specifically to the heart using selective chemogenetic expression of DREADDs in animal models of three distinct cardiovascular diseases: myocardial infarction (MI), pressure overload-induced heart failure (HF), and obstructive sleep apnea (OSA). Furthermore, I investigate the genetic reprogramming caused by restoring cardiac parasympathetic activity, which can be used to focus future investigations of specific mechanisms responsible for the cardioprotection conferred by this treatment paradigm. PVN OXT neuron activation for one-week post-AMI reveals preserved mitochondrial function and reduced myocardial injury based on respiration experiments and analysis of differential gene expression. Ex vivo experiments on Langendorff-perfused hearts from animals with pressure overload-induced HF reveals significant improvements in cardiac function after 12 weeks of chronic activation of PVN OXT neurons. In vivo experiments using implantable telemetry devices to record HR and blood pressure (BP) on animals with induced hypertension undergoing chronic intermittent hypoxia (CIH) exposure, a well- known model for OSA, demonstrates attenuated hypertension and improved autonomic tone with PVN OXT neuron activation; transcriptome analysis reveals reduced pathologic gene expression reprogramming. This dissertation uniquely expands our knowledge of a treatment paradigm with great clinical translational potential for CVDs that targets a specific population of hypothalamic neurons to provide intrinsic cardioprotection to the heart.
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RodriguezGonzalez_gwu_0075A_16112.pdf | 2022-10-04 | Open Access |
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