My research interest centers on elucidating the pathogenic role of endothelial dysfunction in cardiovascular and cardiopulmonary diseases. Our current research focuses on defining the molecular mechanisms involved in coronary microvascular disease with or without diabetes and pulmonary endothelial dysfunction in pulmonary hypertension. Our long-term goal is to find novel druggable molecules to restore endothelial dysfunction and develop effective therapeutic approaches to decrease morbidity and mortality in patients with coronary microvascular disease and pulmonary hypertension. Coronary endothelial dysregulation results in attenuated coronary vasodilation and capillary rarefaction in the heart, ultimately decreasing coronary flow reserve (= coronary microvascular dysfunction) and increasing the incidence of cardiac ischemia and cardiac mortality. My laboratory is among the first to demonstrate the critical role of connexin 40 (Cx40, a gap junction protein), STIM1 (a key player in store-operated calcium entry), p53 (an apoptotic inducer), VDAC and HK2 (a modulator of mitochondrial Ca²⁺ homeostasis), and NAMPT (a damage-associated molecular patterns) in cardiac endothelial dysfunction in diabetes. Our research also revealed that downregulation of Cx40 is involved in the development of pulmonary hypertension, a progressive and potentially fatal disease if untreated. We are a leading team investigating the role of metabolic disease in the development of pulmonary hypertension. In my lab, we use multiple in vitro preparations (e.g., freshly isolated cardiac and pulmonary ECs and 3^rd-4^th order coronary and pulmonary small arteries from mice and rats) and in vivo preclinical animal models (e.g., genetically modified mice and mice with cardiovascular diseases). We also use human ECs and SMCs isolated from the heart and lungs of subjects with diabetes and pulmonary hypertension. We utilize combined techniques (e.g., cardiac hemodynamic measurement, isometric tension measurement, electrophysiology, immunohistochemistry, fluorescence microscopy, high-resolution microscopy, molecular biology, gene sequencing, and bioinformatics) to study pathogenic mechanisms of coronary and pulmonary vascular disease for developing novel therapeutic approaches for coronary microvascular disease and pulmonary hypertension.

Ayako Makino

ACADEMIC POSITIONS