Coronary artery disease (CAD) is a pervasive complicated disease caused by environmental and inherited risk factors and poses a hazard to human beings globally. The incidence rate and the mortality rate have taken on an upward trend in recent years, thereby becoming a major public health issue.
The research team led by Prof. GUAN Minxin from the Zhejiang University Institute of Genetics were the first to construct the Human Umbilical Vein Endothelial Cells (HUVEC) line and detect the deleterious effects of tRNAThr15927G>A mutation that contributes to the pathogenesis of coronary artery disease. These findings are published in the journal of Nucleic Acids Research.
Mitochondria are mighty, microscopic, energy-producing structures that are essential to our health. They are responsible for creating more than 90% of the energy (ATP) needed to sustain life and support organ function. Besides, they’re like tiny factories in each of our cells that produce 95% of the oxygen. In addition to supplying cellular energy, they are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell division cycle and cell growth. Therefore, the proper function of mitochondria is of vital importance to the cardiovascular system.
In 2011, GUAN Minxin participated in a large-scale screening study into mitochondrial mutations among CAD patients in Beijing. In that survey, researchers identified the tRNAThr 15927G>A as the first mtDNA mutation associated with CAD. However, the pathophysiology underlying these tRNA mutations, specifically the tissue specific effect, remains elusive.
(HUVECs) are the most widely used cell models for the study of the regulation of endothelial cell function and the role of the endothelium in the response of the blood vessel wall to stretch, shear forces, and the development of atherosclerotic plaques. GUAN Minxin et al. utilized the HUVECs-derived cybrids to further investigate the pathophysiology of m.15927G>A mutation. These cybrid cell lines were constructed by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family carrying the m.15927G>A mutation and from a control individual lacking the mutation but belonging to the same mtDNA haplogroup into mtDNA-less HUVECs, generated by treatment of rhodamine 6G.
Researchers demonstrated that the m.15927G>A mutation caused significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr. The aberrant tRNAThrmetabolism yielded variable decreases in mtDNA-encoded polypeptides, respiratory deficiency, diminished membrane potential and increased the production of reactive oxygen species.
The m.15927G>A mutation promoted the apoptosis, evidenced by elevated release of cytochrome c into cytosol and increased levels of apoptosis-activated proteins: caspases 3, 7, 9 and PARP. Moreover, the lower wound healing cells and perturbed tube formation were observed in mutant cybrids, indicating altered angiogenesis.
These findings provide new insights into the pathophysiology of coronary artery disease, which is manifested by tRNAThr mutation-induced alterations.