| Summary |
Peripheral artery disease (PAD) is caused by an atherosclerotic blockage to a vessel that restricts blood flow to the lower extremity. Chronic limb threatening ischemia (CLTI) is the most severe manifestation of PAD, and is associated with gangrenous lesions, necrosis, high rates of limb loss, reduced quality of life, and mortality. Despite PAD affecting more than 230 million people worldwide, minimal improvements in patient outcomes have been made over the last two decades (1--4). Therapeutics and endovascular procedures aimed at restoring blood flow have been largely unsuccessful at improving limb outcomes (5--11), particularly in Black patients with CLTI who experience rates of amputation as high as 37% compared with their White counterparts (12). Limb muscle from patients with CLTI exhibit severe myopathy and unique bioenergetic signatures indicative of an inherent or associated muscle response to ischemia (8,13--15). This reinforces the necessity for development of targeted adjuvant therapies to supplement vascular interventions and promote whole tissue regeneration. The aims of this dissertation were to characterize the transcriptomic profile of Black and White patients with CLTI and to determine the role of Bcl-2 associated athanogene 3 (BAG3) in pre-clinical limb ischemia via a multi-compartmental interrogation. This dissertation incorporates previous clinical data on the described racial disparities in PAD manifestation and clinical outcomes and the documented pathologic role of BAG3 mutants that are correlative or causative of striated muscle pathology. The overarching hypotheses of these studies were that: 1) Limb tissue from Black and White patients with CLTI would exhibit distinct transcriptomic profiles from each other and from age/sex/race matched control tissues, and 2, 3) BAG3 is required for cooperative regeneration in both the vascular and skeletal muscle compartments of the ischemic limb and that deletion of BAG3 in either compartment would augment ischemic degeneration of the vasculature and skeletal muscle. Our results reveal a unique transcriptomic profile in the limb tissue of patients with CLTI with significant alterations in genes associated with bioenergetics. We also observed distinct transcriptomic signatures in Black patients with CLTI when compared with race/age matched healthy controls and White patients with CLTI. Preclinically, deletion of BAG3 from the vasculature yielded negligible differences in tissue repair/regeneration, while deletion of BAG3 from skeletal muscle resulted in an enhanced myopathy and a significant delay in blood flow recovery. |
