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Open Access Publications from the University of California

Scholarly Works (36 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2021)
The role of vitamin D in the cardiovascular system is complex because it regulates expression of genes involved in diverse metabolic processes. Although referred to as a vitamin, it is more accurately considered a steroid hormone, because it is produced endogenously in the presence of ultraviolet light. It occurs as a series of sequentially activated forms, here referred to as vitamin D-hormones. A little-known phenomenon, based on pre-clinical data, is that its biodistribution and potential effects on vascular disease likely depend on whether it is derived from diet or sunlight. Diet-derived vitamin D-hormones are carried in the blood, at least in part, in chylomicrons and lipoprotein particles, including low-density lipoprotein. Since low-density lipoprotein is known to accumulate in the artery wall and atherosclerotic plaque, diet-derived vitamin D-hormones may also collect there, and possibly promote the osteochondrogenic mineralization associated with plaque. Also, little known is the fact that the body stores vitamin D-hormones in adipose tissue with a half-life on the order of months, raising doubts about whether the use of the term daily requirement is appropriate. Cardiovascular effects of vitamin D-hormones are controversial, and risk appears to increase with both low and high blood levels. Since low serum vitamin D-hormone concentration is reportedly associated with increased cardiovascular and orthopedic risk, oral supplementation is widely used, often together with calcium supplements. However, meta-analyses show that oral vitamin D-hormone supplementation does not protect against cardiovascular events, findings that are also supported by a randomized controlled trial. These considerations suggest that prevalent recommendations for vitamin D-hormone supplementation for the purpose of cardiovascular protection should be carefully reconsidered.
    Cover page: Potential impact of the steroid hormone, vitamin D, on the vasculature.
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2019)
    Calcific vascular and valvular disease (CVVD) is widespread and has major health consequences. Although coronary artery calcification has long been associated with hyperlipidemia and increased mortality, recent evidence suggests that its progression is increased in association with cholesterol-lowering HMG-CoA reductase inhibitors (statins) and long-term, high-intensity exercise. A nationwide trial showed no cardiovascular benefit of vitamin D supplements. Controversy remains as to whether calcium deposits in plaque promote or prevent plaque rupture. CVVD appears to occur through mechanisms similar to those of intramembranous, endochondral, and osteophytic skeletal bone formation. New evidence implicates autotaxin, endothelial-mesenchymal transformation, and microRNA and long non-coding RNA (lncRNA) as novel regulatory factors. New therapeutic options are being developed.
      Cover page: Interactive and Multifactorial Mechanisms of Calcific Vascular and Valvular Disease.
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2015)
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2016)
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2015)
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2014)
            This review centers on updating the active research area of vascular calcification. This pathology underlies substantial cardiovascular morbidity and mortality, through adverse mechanical effects on vascular compliance, vasomotion, and, most likely, plaque stability. Biomineralization is a complex, regulated process occurring widely throughout nature. Decades ago, its presence in the vasculature was considered a mere curiosity and an unregulated, dystrophic process that does not involve biological mechanisms. Although it remains controversial whether the process has any adaptive value or past evolutionary advantage, substantial advances have been made in understanding the biological mechanisms driving the process. Different types of calcific vasculopathy, such as inflammatory versus metabolic, have parallel mechanisms in skeletal bone calcification, such as intramembranous and endochondral ossification. Recent work has identified important regulatory roles for inflammation, oxidized lipids, elastin, alkaline phosphatase, osteoprogenitor cells, matrix γ-carboxyglutamic acid protein, transglutaminase, osteoclastic regulatory factors, phosphate regulatory hormones and receptors, apoptosis, prelamin A, autophagy, and microvesicles or microparticles similar to the matrix vesicles of skeletal bone. Recent work has uncovered fascinating interactions between matrix γ-carboxyglutamic acid protein, vitamin K, warfarin, and transport proteins. And, lastly, recent breakthroughs in inherited forms of calcific vasculopathy have identified the genes responsible as well as an unexpected overlap of phenotypes. Until recently, vascular calcification was considered a purely degenerative, unregulated process. Since then, investigative groups around the world have identified a wide range of causative mechanisms and regulatory pathways, and some of the recent developments are highlighted in this review.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2014)
              Although epidemiological studies from the past two decades show a link between atherosclerotic vascular disease and bone loss, that is independent of age, the mechanism is still unclear. This review focuses on evidence that suggests a role for atherogenic lipids and lipoproteins in the pathogenesis of bone loss, including direct effects of these bioactive lipids/lipoproteins on bone cells, inhibiting osteoblastic differentiation and promoting osteoclastic differentiation. It also addresses recent evidence that suggests that bioactive lipids blunt the effects of bone anabolic agents such as teriparatide and bone morphogenetic proteins. Systemic and intracellular oxidant stress and inflammation are implicated in mediating the effects of bioactive lipids/lipoproteins.
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2022)
                PURPOSE OF REVIEW: Lipids and lipoproteins have long been known to contribute to atherosclerosis and cardiovascular calcification. One theme of recent work is the study of lipoprotein (a) [Lp(a)], a lipoprotein particle similar to LDL-cholesterol that carries a long apoprotein tail and most of the circulating oxidized phospholipids. RECENT FINDINGS: In-vitro studies show that Lp(a) stimulates osteoblastic differentiation and mineralization of vascular smooth muscle cells, while the association of Lp(a) with coronary artery calcification continues to have varying results, possibly because of the widely varying threshold levels of Lp(a) chosen for association analyses. Another emerging area in the field of cardiovascular calcification is pathological endothelial-to-mesenchymal transition (EndMT), the process whereby endothelial cell transition into multipotent mesenchymal cells, some of which differentiate into osteochondrogenic cells and mineralize. The effects of lipids and lipoproteins on EndMT suggest that they modulate cardiovascular calcification through multiple mechanisms. There are also emerging trends in imaging of calcific vasculopathy, including: intravascular optical coherence tomography for quantifying plaque characteristics, PET with a radiolabeled NaF tracer, with either CT or MRI to detect coronary plaque vulnerability. SUMMARY: Recent work in this field includes studies of Lp(a), EndMT, and new imaging techniques.
                  Cover page: Regulation of cardiovascular calcification by lipids and lipoproteins.
                  • Thesis
                  • Peer Reviewed
                  UCLA Electronic Theses and Dissertations (2019)

                  Cardiovascular development is a highly complex, coordinated process, and the investigation of the mechanisms governing this process has led to the identification of genes that not only orchestrate cardiovascular development, but also modulate disease processes in adulthood. The Notch signaling pathway, for instance, has been shown to orchestrate cardiac valve development during embryogenesis, while also regulating pathological aortic valve calcification in adulthood. Therefore, a deeper understanding of the mechanisms of cardiovascular development can help inform our research into pathophysiological processes such as ectopic calcification. The studies in this dissertation utilize advanced imaging techniques to examine the mechanobiological mechanisms of cardiac valve development and disease.

                  In the first study, four-dimensional light-sheet fluorescence microscopy imaging of embryonic zebrafish hearts was combined with moving-domain computational fluid dynamic modeling to evaluate the relative influences of contractile and hemodynamic shear forces on cardiac valve development. The results showed that contractile forces appear to be necessary for initial cardiac valve formation, whereas hemodynamic shear forces contribute to valve leaflet growth. Further, these processes appear to occur by mechanosensitive, Notch1b-mediated endothelial-to-mesenchymal transition.

                  In the second study, fused 18F-NaF micro-positron emission tomography / micro-computed tomography (uPET/uCT) imaging was performed on aged hyperlipidemic mice to evaluate the effects of an osteoporosis therapeutic drug, teriparatide, on the morphology of aortic calcification. The evidence presented shows that while teriparatide, a parathyroid hormone analog, does not affect the progression of pre-existing aortic calcification, it promotes the coalescence of calcification into macro-calcium deposits. These studies suggest that teriparatide therapy may promote a macrocalcification phenotype in atherosclerotic calcification, with potential implications on plaque stability.

                  In summary, these studies demonstrate the use of advanced imaging modalities, such as light-sheet microscopy and 18F-NaF-uPET/uCT imaging, to investigate the mechanobiological mechanisms of cardiovascular development, as well as cardiovascular disease, such as calcification.

                    Cover page: Light-Sheet Fluorescence Microscopy and Molecular Imaging to Elucidate Mechanisms of Cardiovascular Development and Disease
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2015)
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