Doctor of Philosophy (PhD)
First Advisor's Name
Joshua D. Hutcheson
First Advisor's Committee Title
Second Advisor's Name
Second Advisor's Committee Title
Third Advisor's Name
Third Advisor's Committee Title
Fourth Advisor's Name
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Fifth Advisor's Name
Fifth Advisor's Committee Title
Cardiovascular calcification, Bisphosphonate, Vascular smooth muscle cell, Caveolin-1, Chronic kidney disease, Epidermal growth factor receptor, bone mineralization
Date of Defense
Cardiovascular diseases represent the global leading cause of morbidity and mortality. Cardiovascular calcification is the most significant predictor of cardiovascular events, but no therapeutic options exist to prevent or treat mineral formation in the vasculature. The presence of bone-like mineral increases cardiac work required to move blood through systemic circulation and can lead to mechanical stress in atherosclerotic plaques, promoting plaque rupture events that cause heart attacks. Clinical trials correlated bisphosphonates (BiPs), common anti-osteoporosis pharmaceuticals, with contradicting cardiovascular outcomes. Here, we demonstrated the importance of treatment timing in BiP-induced mineral disruption or promotion. We showed that BiPs can alter morphological features of calcifications within the atherosclerotic plaque of hyperlipidemic mice, which may affect plaque rupture risk.
Osteogenic differentiation of resident vascular smooth muscle cells (VSMCs) and release of calcifying extracellular vesicles (EVs) mediate cardiovascular calcification, which imitates bone mineralization by osteoblasts. Formation of calcifying EVs by VSMCs requires caveolin-1 (CAV1), a scaffolding membrane protein. Targeting cellular mechanisms that involve CAV1 may represent ideal strategies to develop therapeutics for cardiovascular calcification.
We studied the effect of inhibiting several upstream and downstream molecules that are involved in CAV1 activation and trafficking. Interestingly, we showed that altering CAV1 trafficking does not negatively impact physiological mineralization of osteoblasts. We concluded that despite shared mineralization characteristics, the mechanism(s) of bone and vascular calcification is/are distinct.
Furthermore, we demonstrated that epidermal growth factor receptor (EGFR) inhibition prevents vascular calcification by mitigating the biogenesis of calcifying EVs. We showed that EGFR inhibition reduces the release of pro-calcific CAV1-positive EVs and prevents calcification in osteogenic VSMC cultures and in chronic kidney disease mice fed a high-phosphate diet. EGFR inhibitors are clinically approved and widely used in cancer therapies and may represent an appropriate strategy to treat vascular calcification.
Previously Published In
Nik, Amirala Bakhshian, Hooi Hooi Ng, Patrick Sun, Francesco Iacoviello, Paul R. Shearing, Sergio Bertazzo, Deniel Mero, Bohdan B. Khomtchouk, and Joshua D. Hutcheson. "Epidermal Growth Factor Receptor Inhibition Prevents Caveolin-1-dependent Calcifying Extracellular Vesicle Biogenesis." bioRxiv (2021).
Bakhshian Nik, Amirala, Joshua D. Hutcheson, and Elena Aikawa. "Extracellular vesicles as mediators of cardiovascular calcification." Frontiers in cardiovascular medicine 4 (2017): 78.
Bakhshiannik, Amirala, "Therapeutic Approaches to Alter Mineral Formation and Growth in Vascular Calcification" (2022). FIU Electronic Theses and Dissertations. 4932.
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