1: Social Bonds Retain Oxytocin-Mediated Brain-Liver Axis to Retard Atherosclerosis.
Science of the Month - February 2025
Ko S, Anzai A, Liu X, Kinouchi K, Yamanoi K, Torimitsu T, Ichihara G, Kitakata H, Shirakawa K, Katsumata Y, Endo J, Hayashi K, Yoshida M, Nishimori K, Tanaka KF, Onaka T, Sano M, Ieda M.
In recent years, clinical studies in humans have reported that social isolation increases the incidence of atherosclerotic diseases such as myocardial infarction and all-cause mortality, but the detailed mechanisms have remained unclear. Using an animal model, we conducted a cross-organ investigation and found that social isolation stress promotes atherosclerosis, independent of previously presumed factors such as increased food intake and body weight, or activation of the sympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and inflammation. We also revealed that social isolation reduces oxytocin secretion from the hypothalamus and simultaneously exacerbates dyslipidemia, characterized by elevated triglycerides and bad cholesterol. In this study, we discovered that oxytocin receptors are expressed in hepatocytes and, for the first time in the world, reported that oxytocin regulates hepatic and systemic lipid metabolism through two distinct pathways: bile acid production via CYP7A1 and regulation of lipoprotein lipase activity via ANGPTL4/8. Furthermore, we confirmed that oral supplementation of oxytocin suppresses the lipid metabolism abnormalities and progression of atherosclerosis caused by social isolation stress. This research indicates that oxytocin, known as the "happiness hormone," is a promising new therapeutic target molecule for atherosclerosis progression due to loneliness. It may also help elucidate the mechanisms by which rich social connections contribute to maintaining human health.
(Atsushi Anzai, Class of '84, and Seong-Beom Ko, Class of '92, Department of Cardiology)
2:Cardiac reprogramming and Gata4 overexpression reduce fibrosis and improve diastolic dysfunction in heart failure with preserved ejection fraction
Circulation.
Yu Yamada #, Taketaro Sadahiro #, Koji Nakano, Seiichiro Honda, Yuto Abe, Tatsuya Akiyama, Ryo Fujita, Masashi Nakamura, Takashi Maeda, Yuta Kuze, Masaya Onishi, Masahide Seki, Yutaka Suzuki, Chikara Takeuchi, Yuka W Iwasaki, Kensaku Murano, Mamiko Sakata-Yanagimoto, Shigeru Chiba, Hideyuki Kato, Hiroaki Sakamoto, Yuji Hiramatsu, Masaki Ieda
Heart transplantation, the definitive treatment for severe heart failure, which is the end stage of heart disease, is difficult to provide sufficiently due to issues such as donor shortages. As a potential solution to these challenges, we developed "cardiac direct reprogramming" to directly induce cardiomyocytes from cardiac fibroblasts. We succeeded in cardiac regeneration and improving cardiac fibrosis and cardiac function in a myocardial infarction mouse model and in a mouse model of heart failure with reduced ejection fraction. Heart failure is divided into heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. However, it was unknown whether this method could be applied to heart failure with preserved ejection fraction, for which no effective treatment exists. Therefore, we developed a genetically modified mouse in which the expression of cardiac reprogramming genes in cardiac fibroblasts can be controlled by drug administration. We demonstrated for the first time in the world that cardiac direct reprogramming can regenerate cardiomyocytes from fibroblasts in heart failure with preserved ejection fraction, improving cardiac fibrosis and cardiac function. Furthermore, we discovered that Gata4, one of the cardiac reprogramming genes, is crucial for treating cardiac fibrosis. We developed a treatment for heart failure with preserved ejection fraction through the improvement of cardiac fibrosis, achieved by the gene transfer of Gata4 alone.
(Taketaro Sadahiro, Class of '86, Department of Cardiology)
Other Published Papers
1: Regeneration of Nonhuman Primate Hearts With Human Induced Pluripotent Stem Cell-Derived Cardiac Spheroids.
Circulation.
Kobayashi H, Tohyama S, Ohashi N, Ichimura H, Chino S, Soma Y, Tani H, Tanaka Y, Yang X, Shiba N, Kadota S, Haga K, Moriwaki T, Morita-Umei Y, Umei TC, Sekine O, Kishino Y, Kanazawa H, Kawagishi H, Yamada M, Narita K, Naito T, Seto T, Kuwahara K, Shiba Y, Fukuda K.