Our collaborative team has established that the mechanisms of flow-mediated dilation (FMD) changes over the lifespan and shift with the onset of CAD. In healthy patients, FMD is regulated by the vasoprotective dilator nitric oxide (NO). In contrast, in CAD patients or in vessels exposed to acute stressors, NO bioavailability is reduced, and FMD is attributed to a compensatory rise in hydrogen peroxide (H2O2), a pro-inflammatory reactive oxygen species (ROS). These findings expanded our understanding of CAD, which was previously viewed as a disease limited to large conduit arteries, to reflect microvascular pathology to with significant prognostic implications. Our studies pioneered genetic manipulation techniques (siRNA, viral overexpression) in the human coronary circulation to answer mechanistic questions.
Work in my lab has long integrated animal studies with mechanistic evaluation of isolated human microvessels. Recent collaborative projects led us to expand our repertoire to study vascular function in vivo (e.g., brachial artery FMD, arterial tonometry, echocardiography, skin microdialysis/laser Doppler flowmetry). Our work fulfills a critical need to translate preclinical findings into human studies and thus serves as a bridge to clinical investigations. Understanding the molecular and physiological changes that contribute to CVD has clinical implications that, may lead to novel means to predict pathological changes and intervene before irreversible damage occurs.
Current work in understanding the pathological changes that occur with onset of CAD focuses on the role of TERT, the catalytic subunit of telomerase, in maintaining vasodilator function in the human microcirculation. Specifically, we study a noncanonical role of TERT in preserving mitochondrial homeostasis. We discovered previously unrecognized signaling between TERT and well-known regulators of vascular health, such as the renin angiotensin system and autophagy. Data from my lab and that of others implicate decreased levels of TERT with elevated mitochondrial DNA (mtDNA) damage as important regulators of mitochondrial integrity. This evidence led to a new collaborative work designed to understand the contribution of mitochondrial networks and their regulation to pathological changes in the human microcirculation. In specific, we aim to define how mitochondrial fission and fusion and its regulation, a fundamental process to maintain mitochondrial and cellular health, is critically linked as a regulator of FMD in the human microcirculation.
Fig. 1. Mitochondrial integrity and microvascular function.
Cardiovascular disease (CVD) and cancer are the number one and two causes of mortality and morbidity, and it is increasingly recognized that cancer and CVD share overlapping risk profiles. Long-term cancer survival is closely tied to CVD, while CVD conditions contribute to the progression of cancer and influence relevant treatment choices. With the use of systemic and targeted anti-cancer therapies (CTx), the number of annual deaths from cancer has been significantly reduced; however, most CTx agents have severe adverse consequences for the cardiovascular system. In fact, CVD related to CTx has emerged as the leading cause of non-cancer related deaths among breast cancer (BC) survivors. Given the magnitude of the clinical problem of cardiovascular-related mortality in cancer survivors, the novel clinical field of cardio-oncology has emerged with the aim of improving long-term, disease-free survival in cancer patients while addressing the underlying mechanism of cardiovascular comorbidity. While injury to the heart resulting from exposure to CTx is well established, little data exist on the contribution of CTx to endothelial cell dysfunction and the direct effect on mitochondria in the microcirculation. Microvascular endothelial dysfunction is the best predictor of future cardiovascular events, superior even to the degree of large vessel disease (i.e., CAD (coronary artery disease)) or ejection fraction in patients with or without coronary stenoses. This suggests that understanding the long-term consequences of CTx on microvascular function represents a novel, to date mostly unexplored, avenue to understanding and predicting the risk of cardiovascular complications in cancer patients.
We are using lessons learned from our ongoing investigations in understanding the changes in microvascular function in patients with CAD and expand them to investigate the vascular and mitochondrial changes and systemic consequences in cancer patients undergoing clinical necessary anti-cancer therapy. The objectives of this proposal are to 1) establish the contribution of microvascular dysfunction to CVD progression with an emphasis on cardio-oncology; 2) Establish the relevance of mitochondrial damage and secondary signaling in development and progression of CV events in cancer survivors; 3) define and predict risk for adverse CV events in cancer patients building on concepts of systems biology.
Fig. 3. CTx-induced mitochondrial damage and secondary signaling.
- Critical Role of Mitochondrial Fission/Fusion in Regulation of Microvascular Endothelial Function
- Understanding and Addressing Cancer Therapy Induced Systemic Inflammation and Associated Endothelial Dysfunction. Clinical Project Defining Differences in Endothelial Function and Response to CTx among a Diverse Population of Women with BC
- Pivotal Role of Mitochondrial Telomerase in Regulation of Vascular Tone and Redox Homeostasis
- Differentiation of mitochondrial vs. nuclear function of telomerase
- Karima Ait-Aissa
- Daniela Didier
- Johnathan Ebben
- Alena Hanson
- Joe Hockenberry
- Andrew D. Kadlec, PhD
- Minhi Kang
- Todd Le
- Jasmine Linn
- Micaela Young
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