Shaping Cardiac Immuno-metabolic Homeostasis by the Lysosome

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) accounts for half of the heart failure hospitalizations in the US thus representing a major public health priority. However, currently, there are limited effective approaches to preventing and managing this complex syndrome. Systemically, obesity-associated hyperlipidemia, hyperglycemia, and chronic inflammation have been considered as the major factors for the pathogenesis of HFpEF. In the heart, maladaptive cardiac immuno-metabolic reprogramming is a hallmark of HFpEF. In cells, nutrient sensing, macromolecule catabolism, and inflammatory regulation are fine-tuned by the lysosome. However, the extent and mechanisms by which lysosomal dysfunction contributes to the pathogenesis of HEpEF are poorly defined. The objective of this proposal is to determine the pathophysiological impact of cardiac lysosomal dysfunction in the setting of HFpEF. The lysosome contains more than 70 enzymes. As such, murine studies of individual lysosomal enzymes have contradicting observations regarding cardiac pathophysiology. Lysosomal reductase Gamma Interferon-Inducible Thiol Reductase (GILT) is the only identified lysosomal reductase that controls diverse sets of lysosomal enzymes and cargoes. We found that GILT is reduced in the hearts of humans with HFpEF and obese mice, respectively. Notably, both lean and obese mice with a human GILT SNP for CVD risk displayed a significantly reduced diastolic function without other interventions. Furthermore, loss of GILT in cardiomyocytes accelerates the HFpEF-related cardiac decline. Transcriptomic and metabolic analyses further revealed that cardiac GILT deficiency disrupted the immuno-metabolic homeostasis in the heart. Therefore, we hypothesize that GILT protects against cardiac immuno-metabolic imbalance in obesity-associated HFpEF. We will pursue two specific aims to test this hypothesis. In Aim 1, we will investigate the pathological significance of cardiac GILT in the context of HFpEF by using novel gain- or loss-function of GILT mouse lines. In Aim 2, we will elucidate molecular mechanisms for cardiomyocyte GILT-regulated mitochondrial function, glucose homeostasis, and inflammasome activation. To answer these challenging questions, we have assembled a strong collaborative team. Each co-PI is a recognized expert in her/his respective field (organelle functions in obesity, cardiac pathophysiology, and cardiac metabolism). This collaborative research proposal is innovative, combining the use of cellular and molecular approaches, metabolomic analyses, as well as in vivo mouse metabolic and cardiac profiling. Findings from this study will provide insights into interplays between cardiac lysosomes, inflammatory responses, and metabolic homeostasis and should speed the development of novel therapies for improving cardiovascular health.