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Ayako Makino, PhD
Research in our laboratory centers on the modulation of endothelium function in the pathological state. Vascular endothelial cells play critical roles in vascular function such as anticoagulant barrier formation between blood and the vascular wall, regulation of vascular tone, and new vessel formation. In many cardiovascular diseases, endothelial cells are injured and/or dysfunctional, which leads to subsequent vascular complications. In our laboratory, we investigate cellular and molecular mechanisms of coronary vascular endothelial dysfunction in diabetes, focusing on vascular rarefaction and attenuated vascular relaxation.
Ongoing research projects in the lab:
1) Mitochondrial autophagy (mitophagy) in endothelial cells
We recently demonstrated that mitochondria in coronary endothelial cells in diabetic mice are more apoptotic than in controls. We investigate the relationship between mitophagy and endothelial apoptosis in diabetes.
2) Ca2+ homeostasis in endothelial cells
Our previous studies indicated that Ca2+ release from the endoplasmic reticulum is decreased and mitochondrial Ca2+ concentration is increased in coronary endothelial cells isolated from diabetic mice. Our current research is focused on defining the molecular mechanisms by which hyperglycemia regulates Ca2+ homeostasis in endothelial cells.
3) GAP junction intercellular communication (GJIC) between endothelial cells
We demonstrated that coronary endothelial cells isolated from diabetic mice exhibit attenuated GJIC and decreased protein expression level of connexin 40 (one of the GAP junction components). We are currently investigating the upstream mechanisms that regulate connexin40 protein expression and the potential effect of connexin40 overexpression on vascular endothelial cell function in diabetic mice.
In our lab, we use multiple preparations (e.g., freshly isolated endothelial cells, dissected vascular vessels, and a whole heart) and combined techniques (e.g., isometric tension measurement, electrophysiology, immunohistochemistry, fluorescence microscopy, and molecular biology) to study endothelium functions.
Selected Publications (last 5 years):
1. Cho YE, Basu A, Dai A, Heldak M, and Makino A. Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice. Am. J. Physiol. Cell Physiol. 305(10):C1033-40. 2013.
2. Yamamura A, Yamamura H, Guo Q, Zimnicka AM, Wan J, Ko EA, Smith KA, Pohl NM, Song S, Zeifman A, Makino A, and Yuan JX. Dihydropyridine Ca2+ channel blockers increase cytosolic [Ca2+] by activating Ca2+-sensing receptors in pulmonary arterial smooth muscle cells. Circ Res. 112(4):640-50. 2013.
3. Estrada IA, Donthamsetty R, Debski P, Zhou M-H, Zhang SL, Yuan JX, Han W and Makino A. STIM1 restores coronary endothelial function in type1 diabetic mice. Circ. Res. 111(9):1166-1175. 2012.
4. Yue L, Phillips S, Bian J-T, Makino A, and Mazzone T. Macrophage-derived ApoE co-localizes with endothelial cell cav-1 to modulate its association with eNOS and regulate NO production. Hypertension. 60(4):1040-6. 2012.
5. Sasaki K, Donthamsetty R, Heldak M, Scott BT, Makino A. VDAC: An old protein with new roles in diabetes. Am. J. Physiol. Cell Physiol. 303(10):C1055–C1060. 2012.
6. Shentu T-P, Singh DK, Oh M-J, Sun S, Sadaat L, Makino A, Mazzone T, Subbaiah P, Cho M, and Levitan I. The role of oxysterols in control of endothelial stiffness. J. Lipid Res. 53(7):1348-1358, 2012.
7. Makino A, Wang H, Scott BT, Yuan JX, and Dillmann WH. Thyroid Hormone Receptor α and Vascular Function. Am. J. Physiol. Cell Physiol. 302:C1346-C1352, 2012.
8. Yao W, Mu W, Zeifman A, Lofti M, Remillard CV, Makino A, Perkins DL, Garcia J.G.N., Yuan JX, and Zhang W. Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm. Circ. (3):405-418, 2011.
9. Makino A, Suarez J, Gawlowski T, Han W, Wang H, Scott BT, and Dillmann WH. Regulation of Mitochondrial Morphology and Function by O-GlcNAcylation in Neonatal Cardiac Myocytes. Am. J. Physiol. Regul. Integr. Comp. Physio.300:R1296-R1302, 2011.
10. Song MY, Makino A, and Yuan JX. STIM2 contributes to enhanced store-operated Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Pulm. Circ. 1:84-94, 2011.
11. Makino A, Scott BT, and Dillmann WH. Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 53(8):1783-1794, 2010.
12. Makino A, Suarez J, Wang H, Belke DD, Scott B and Dillmann WH. Thyroid hormone receptor β is associated with coronary angiogenesis during pathological cardiac hypertrophy. Endocrinology 150:2008-2015, 2009.
13. Li X, Zhang X, Leathers R, Makino A, Huang C, Parsa P, Marcias J, Yuan JX, Jamieson SW and Thistlethwaite PA. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat. Med. 15(11):1289-1297, 2009.
14. Makino A, Platoshyn O, Suarez J, Yuan JX and Dillmann WH. Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice. Am. J. Physiol. Cell Physiol. 295:221-230. 2008.
15. Suarez J, Hu Y, Makino A, Fricovsky E, Wang H, and Dillmann WH. Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes. Am. J. Physiol. Cell Physiol. 295:C1561-C1568, 2008.