Dennis Wang Laboratory
Heart failure (HF) is a complex, multifaceted condition that involves not only the cardiovascular system but also a dynamic interplay of metabolic and immune processes. One of the central drivers of HF is inflammation, particularly a type of sterile inflammation that arises in the absence of infection. This inflammatory response is often triggered by cellular stress and mitochondrial dysfunction, which release proinflammatory signals into the bloodstream. My research is focused on unraveling the mechanisms behind this inflammation, particularly the role that mitochondrial dysfunction plays in driving immune activation. Through a combination of molecular, cellular, and therapeutic investigations, we aim to uncover new insights into how inflammation fuels HF progression and explore potential treatments to mitigate these effects.
Contact
Email: ddwang2@uw.edu
Phone: 206-616-6256
Address: 850 Republican Street, Room N130 (SLU), Box 358057, Seattle, Washington 98109-8057
Role of Mitochondria-Containing Extracellular Vesicles (MitoEVs) in Heart Failure Inflammation
Our research has revealed that mitochondria-containing extracellular vesicles (MitoEVs) play a significant role in driving the inflammatory processes in heart failure (HF). We identified that patients with HF have elevated levels of MitoEVs, which carry mitochondrial components capable of triggering immune responses. These vesicles, primarily released by CD14+ monocytes, propagate inflammatory signals, contributing to the worsening of HF. Through advanced imaging and biochemical techniques, we discovered that MitoEVs are immunogenic, with their release being closely linked to mitochondrial dysfunction and impaired autophagy. This finding is crucial, as it underscores the involvement of MitoEVs in amplifying sterile inflammation—a key feature in the progression of heart failure
Exploring Mitochondrial Dysfunction in Heart Failure
In earlier studies, we focused on the pivotal role of mitochondrial dysfunction in the pathophysiology of HF. Mitochondrial damage-associated molecular patterns (MitoDAMPs) and other mitochondrial byproducts are released during cellular stress, activating the NLRP3 inflammasome and driving the release of proinflammatory cytokines, such as IL-1B and IL-6. These cytokines exacerbate the inflammatory state in HF, contributing to tissue damage and worsening clinical outcomes. By studying peripheral immune cells, particularly monocytes, we showed that HF patients exhibit reduced mitochondrial respiratory function, which further drives systemic inflammation. This foundational work has provided new insights into how mitochondrial dysfunction can be both a cause and a consequence of inflammation in heart failure.
Therapeutic Potential of NAD+ Augmentation
Building on these mechanistic insights, our current research has turned towards therapeutic interventions that target mitochondrial dysfunction. We demonstrated that supplementation with nicotinamide riboside (NR), a precursor of NAD+, can significantly improve mitochondrial respiration and reduce inflammatory signaling in HF. By boosting NAD+ levels, we observed a reduction in the release of MitoEVs and a suppression of the NLRP3 inflammasome activity. This dual effect not only improves mitochondrial function but also dampens the inflammatory response driven by damaged mitochondria. Importantly, NR supplementation has shown potential in reducing IL-1B production, a key mediator of inflammation in HF. These findings highlight NAD+ augmentation as a promising therapeutic approach for mitigating mitochondrial-induced inflammation in HF and suggest new avenues for slowing disease progression.
Postdoc Fellow
The Dennis Wang Laboratory is recruiting highly motivated postdoc fellows to lead projects on molecular mechanisms linking cell metabolism and mitochondrial function to the development of human diseases.
Lab Members
Dennis Wang, MD, PhD
- Assistant Professor, Division of Cardiology
- Mitochondria and Metabolism Center
206-543-8982
