Wang, T., Garcia, J. G., & Zhang, W. (2012). Epigenetic Regulation in Particulate Matter-Mediated Cardiopulmonary Toxicities: A Systems Biology Perspective. Current pharmacogenomics and personalized medicine, 10(4), 314-321.
Particulate matter (PM) air pollution exerts significant adverse health effects in global populations, particularly in developing countries with extensive air pollution. Understanding of the mechanisms of PM-induced health effects including the risk for cardiovascular diseases remains limited. In addition to the direct cellular physiological responses such as mitochondrial dysfunction and oxidative stress, PM mediates remarkable dysregulation of gene expression, especially in cardiovascular tissues. The PM-mediated gene dysregulation is likely to be a complex mechanism affected by various genetic and non-genetic factors. Notably, PM is known to alter epigenetic markers (e.g., DNA methylation and histone modifications), which may contribute to air pollution-mediated health consequences including the risk for cardiovascular diseases. Notably, epigenetic changes induced by ambient PM exposure have emerged to play a critical role in gene regulation. Though the underlying mechanism(s) are not completely clear, the available evidence suggests that the modulated activities of DNA methyltransferase (DNMT), histone acetylase (HAT) and histone deacetylase (HDAC) may contribute to the epigenetic changes induced by PM or PM-related chemicals. By employing genome-wide epigenomic and systems biology approaches, PM toxicogenomics could conceivably progress greatly with the potential identification of individual epigenetic loci associated with dysregulated gene expression after PM exposure, as well the interactions between epigenetic pathways and PM. Furthermore, novel therapeutic targets based on epigenetic markers could be identified through future epigenomic studies on PM-mediated cardiopulmonary toxicities. These considerations collectively inform the future population health applications of genomics in developing countries while benefiting global personalized medicine at the same time.
Yuan, J., Makino, A., Garcia, J. G., Mcdermott, K. M., Rischard, F., Desai, A., Black, S., Khalpey, Z. I., Cordery, A. G., Sun, X., Tang, H., Babicheva, A., Dash, S., Yamamura, H., Yamamura, A., Ayon, R. J., & Song, S. (2017). Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. American journal of physiology. Lung cellular and molecular physiology, 312(3), L309-L325.
Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that a capsaicin-induced increase in [Ca2+]cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs from healthy donors. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23 to 43°C, or decreasing the extracellular pH value from 7.4 to 5.9 enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca2+]cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing the extracellular osmotic pressure from 310 to 200 mOsmol/l also increased [Ca2+]cyt, and the hypo-osmolarity-induced rise in [Ca2+]cyt was greater in IPAH PASMCs than in healthy PASMCs. Inhibition of TRPV1 (with 5'-IRTX or capsazepine) or knockdown of TRPV1 (with short hairpin RNA) attenuated capsaicin-, acidity-, and osmotic stretch-mediated [Ca2+]cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca2+]cyt, and capsaicin-induced CREB phosphorylation were significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMC proliferation. Taken together, the capsaicin-mediated [Ca2+]cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca2+ influx and excessive PASMC proliferation in patients with IPAH.
Khalpey, Z. I., Smolenski, R. T., Runyan, R. B., Smith, R., Garcia, J. G., Maltais, S. S., Schmitto, J. D., Beaudry, C., Desai, A., Betterton, E. A., Johnson, K., Dicken, D. S., Pilikian, T., Sweitzer, N. K., & Mikail, P. (2017). Stem cell-liquid matrix therapy may provide a bridge to regeneration in patients with cardiac mechanical circulatory support. Journal of Heart and Lung Transplantation..
Desai, A., Garcia, J. G., Yuan, J., Jacobson, J. J., Nair, V., Mitra, S., Tang, H., Gupta, G., & Gupta, A. (2017). Inhibition of the deubiquitinase, UCHL1, attenuates pulmonary hypertension.. American J Respiratory Critical Care Medicine.
Gross, C., Kellner, M., Wang, T., Lu, Q., Sun, X., Kangath, A., Zemskov, E., Kumar, S., Desai, A., Aggarwal, S., Golchov, B., Klinger, C., Verin, A. D., Catravas, J. D., Jacobsen, J. R., Yuan, J., Rafikov, R., Garcia, J. G., & Black, S. (2016). Lipopolysaccharide Induced Acute Lung Injury Involves the Nuclear Factor Kappa B Mediated Downregulation of the Transcription Factor SOX-18. Am J Respir Cell Mol Biol..