Cutting edge Seminar

 

 

Speaker:  Yoko Yoshida  (Program Specific Associate Professor, Department of Cardiovascular Biology
and Medicine, Juntendo University Graduate School of Medicine)

Title:  The role of cellular senescence in the pathologies of cardiovascular-metabolic diseases.

 

 

 

※This seminar can also be attended through ZOOM. Please check the URL on “HIGO Cutting-Edge Seminar” at Moodle.

https://md.kumamoto-u.ac.jp/course/view.php?id=95315

 

 

Abstract:

Aging is one of chief risk factors for cardiovascular-metabolic diseases such as heart failure, obesity and diabetes. Accumulating evidence has indicated the close link between cellular senescence and these aging-related diseases. It is also known that adipose tissue inflammation associated with obesity is involved in the development and progression of systemic insulin resistance and diabetes mellitus. We previously demonstrated that excessive calorie intake induced p53-dependent adipose tissue aging, which led to systemic insulin resistance. In addition, we found that p53 up-regulated semaphoring 3E (Sema3E) and the Sema3E- plexinD1 axis is crucial for the development of adipose tissue inflammation that leads to systemic insulin resistance. Sema3E recruited plexinD1-positive macrophages. Activation of adipose tissue p53 positively regulated Sema3E-induced infiltration of macrophages into visceral fat, leading to adipose tissue inflammation and metabolic abnormalities associated with dietary obesity. Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure (HF), but the underlying mechanisms have not been fully elucidated. We previously showed that p53-induced adipose tissue inflammation is critically involved in insulin resistance during HF and that inhibition of adipose tissue p53 improves the progression of cardiac dysfunction as well as metabolic abnormalities. HF markedly up-regulated p53 expression in adipose tissue in association with an increase of adipose

tissue inflammation. Increased sympathetic activity promoted lipolysis that led to accumulation of oxidative stress and DNA damage resulting in p53-dependent adipose inflammation and insulin resistance via the NF-kB-dependent pathway. Disruption of p53 activation in adipose tissue ameliorated inflammation in this tissue and improved insulin resistance, but also improved cardiac dysfunction associated with HF. We also demonstrated that activation of the sympathetic nervous system during HF promoted cardiac inflammation by up-regulating ICAM1 and integrin expression via p53 activation to exacerbate cardiac dysfunction. These data suggests that p53-dependent aging has a crucial role for the progression of cardiovascular-metabolic disorders and inhibition of cellular senescence could be a novel therapeutic strategy to block these diseases.

 

Reference:

1. Shimizu I*, Yoshida Y*, Moriya J*, Nojima A, Uemura A, Kobayashi Y, Minamino T. Semaphorin-induced inflammation contributes to insulin resistance in dietary obesity. Cell Metab. 2013; 18: 1-14. *Co-first authors.

2. Shimizu I*, Yoshida Y*, Katsuno T, Tateno K, Okada S, Moriya J, Yokoyama M, Nojima A, Ito T, Zechner R, Komuro I, Kobayashi Y, Minamino T. p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. Cell Metab 2012; 15: 51-64. *Co-first authors.

3. Yoshida Y, Shimizu I, Katsuumi G, Suda M, Hayashi Y, Minamino T. p53-induced inflammation exacerbates cardiac dysfunction during pressure overload. J Mol Cell Cardiol. 2015; 85: 183-198.

4. Yoshida Y, Shimizu I, Shimada A, Nakahara K, Yanagisawa S, Kubo M, Fukuda S, Ishii C, Yamamoto H, Ishikawa T, Kano K, Aoki J, Katsuumi G, Suda M, Ozaki K, Yoshida Y, Okuda S, Ohta S, Okamoto S, Minokoshi Y, Oda K, Sasaoka T, Abe M, Sakimura K, Kubota Y, Yoshimura N, Kajimura K, Zuriaga M, Walsh K, Soga T, Minamino T. Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N‐oxide‐dependent mechanism. Sci Rep. 12(1):14883, 2022.