Wednesday, December 4, 2024
12/4/2024
Project Summary Ventricular arrhythmia is the leading cause of death for chronic heart failure (CHF) patients. Although the therapeutic potential of renal denervation (RDN) for ventricular arrhythmias has been reported extensively, RDN- induced adverse complications severely limit its use in the clinic. Our recent study revealed that macrophage expansion and neuroinflammation in the stellate ganglion (SG) contribute to CHF-increased cell excitability of cardiac sympathetic postganglionic (CSP) neurons, which subsequently promotes cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF rats. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a crucial mediator in macrophage activation. Our pilot data showed that RDN attenuates cardiac sympathetic overactivation and ventricular arrhythmias, which are accompanied by the marked reduction of GM- CSF level and macrophage activation in SGs in CHF rats. However, it remains unclear if the antiarrhythmic effect of RDN is achieved via attenuating GM-CSF-mediated inflammatory pathways in SGs in CHF. Following the discovery of the antiarrhythmic mechanisms of RDN, this proposal aims to develop a novel clinical intervention to achieve the therapeutic role of RDN and avoid its limitations. Since sympathetic innervation of the kidney originates primarily from neurons in the aorticorenal ganglion (ARG), targeting ARG neurons could be a logical therapeutic strategy for achieving the antiarrhythmic role of RDN. Considering the advantages of optogenetics, including rapid, specific control of neuronal activities by light-sensitive opsins, adeno-associated-virus- Archaerhodopsin (ArchT, an inhibitory light-sensitive opsin) gene will be transfected into ARG neurons in CHF rats. Specificity of neuronal expression of ArchT in ARG neurons will be achieved by linking a neuron-specific promoter to the ArchT gene. Continual optogenetic silencing in ARG neurons will be achieved by illuminating a LED probe that is controlled and powered wirelessly in freely moving animals. We hypothesize that optogenetic inhibition of ARG neurons would reduce CHF-elevated GM-CSF level in SGs, which subsequently alleviates macrophage activation and neuroinflammation in SGs, thereby attenuating CSP neuronal excitability, cardiac sympathetic overactivation, and ventricular arrhythmogenesis in CHF. Using multi-faceted technical approaches ranging from whole-animals to cellular-molecular levels, we will design in vivo and in vitro studies to assess these questions. Specific Aim 1, we will test if GM-CSF signaling axis contributes to macrophage activation and neuroinflammation in SGs from CHF animals. Specific Aim 2, we will address if GM-CSF signaling pathway contributes to CHF-increased cell excitability of CSP neurons, cardiac sympathetic overactivation, and ventricular arrhythmogenesis. Specific Aim 3, we will determine if optogenetic silencing in ARGs can achieve the antiarrhythmic effect of RDN by attenuating GM-CSF-induced macrophage activation and neuroinflammation in SGs in CHF. These studies will open a new avenue in therapeutics against lethal ventricular arrhythmia and provide a novel clinical intervention to reduce mortality and improve outcomes and quality of life in CHF patients.
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