Research Paper|Volume 15, Issue 23|pp 14019—14038

Rewiring of IGF1 secretion and enhanced IGF1R signaling induced by co-chaperone carboxyl-terminus of Hsp70 interacting protein in adipose-derived stem cells provide augmented cardioprotection in aging-hypertensive rats

Parthasarathi Barik¹, Wei-Wen Kuo², Chia-Hua Kuo³, Dennis Jine-Yuan Hsieh^4,⁵, Cecilia Hsuan Day⁶, Jayasimharayalu Daddam⁷, Michael Yu-Chih Chen⁸, V. Vijaya Padma⁹, Marthandam Asokan Shibu⁹, Chih-Yang Huang^1,^7,^10,^11,¹²

¹Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
²Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
³Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
⁴School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
⁵Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
⁶Department of Nursing, Mei Ho University, Pingtung, Taiwan
⁷Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
⁸Department of Cardiology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
⁹Department of Biotechnology, Bharathiar University, Coimbatore, India
¹⁰Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
¹¹Department of Biotechnology, Asia University, Taichung, Taiwan
¹²Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan

* Equal contribution

Received: September 1, 2021Accepted: October 4, 2023Published: December 11, 2023

https://doi.org/10.18632/aging.205287

Copyright: © 2023 Barik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aging-associated cardiovascular diseases depend on the longitudinal deterioration of stem cell dynamics. The entire mechanism behind it is not completely understood. However, many studies suggest that endocrine pathways, particularly the insulin-like growth factor-1(IGF1) signaling pathway are involved in cardioprotection, especially in stem-cell treatments. Here, we investigated the role of a co-chaperone, carboxyl-terminus of Hsp70 interacting protein (CHIP) in the aspects of growth factor secretion and receptor stabilization in mesenchymal stem cells (MSCs). Briefly, we overexpressed CHIP in rat adipose-derived stem cells (rADSCs) and explored the consequences in vitro, and in vivo, in spontaneously hypertensive rats (SHR). Our data revealed that CHIP overexpression in rADSCs promoted the secretion of insulin-like growth factor-1 (IGF1) and IGF binding protein-3 (IGFBP3) as per immunoblot/cytokine array analysis. We also found that these results were dependent on the nuclear translocation of signal transducer and activator of transcription 3 (STAT3) in rADSCs. Further, the CHIP co-chaperone was also involved in the stabilization of the receptor of IGF1 (IGF1R); interactions between the beta transmembrane region of IGF1R, and the tetracopeptide repeat (TPR) domain of CHIP were evident. Importantly, after the transplantation of lentiviral CHIP overexpression of rADSCs (rADSCs^CHIP-WT) into nine months aging-SHR led to an increase in their cardiac function - increased ejection fraction and fractional shortening (≈15% vs. control SHR) - as well as a decrease in their heart size and heart rate, respectively. Altogether, our results support the use of CHIP overexpressing stem cells for the mitigation of cardiac hypertrophy and remodeling associated with late-stage hypertension.