Sidong Cai

The University of Hong Kong-Shenzhen Hospital, China

Exploring the Protective Mechanism of the Ovary Against Heart Failure with Preserved Ejection Fraction from the Perspective of IGF1-Estrogen-CPT1A Signal Axis

Biography

Sidong Cai is currently a Research Associate in the Cardiology Division of the Department of Medicine at The University of Hong Kong-Shenzhen Hospital and an Honorary Research Associate at The University of Hong Kong since January 2025. He obtained a Bachelor's degree in Pharmaceutical Engineering from Guangzhou University of Chinese Medicine in 2015, followed by a Doctorate in Pharmacology from Sun Yat-sen University in December 2020.Following the completion of the doctoral program, He served as a Postdoctoral Fellow from February 2021 to December 2023 at both The University of Hong Kong-Shenzhen Hospital and the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences. In January 2024, He was appointed as an Assistant Researcher at The University of Hong Kong-Shenzhen Hospital. His research interests lie primarily in cardiovascular pharmacology and translational medicine, contributing to the advancement of therapeutic strategies within the field of cardiology.

Abstract

Objective: This study aims to investigate the protective effects of insulin-like growth factor 1 (IGF1) against heart failure with preserved ejection fraction (HFpEF), validate the ovary as the pivotal organ mediating IGF1’s anti-HFpEF role, elucidate the mechanism by which estrogen regulates carnitine palmitoyltransferase 1A (CPT1A) transcription through cardiac estrogen receptor ? (ER?), identify key fatty acids modulated by the IGF1/estrogen/CPT1A axis, and explore the clinical utility of serum IGF1 as a diagnostic biomarker for HFpEF.

Scope: Mechanistic and functional analysis of IGF1 in HFpEF, with a focus on ovarian-dependent signaling pathways.

Results: Exogenous IGF1 administration improved cardiac function in HFpEF mice, but the effect was abrogated by ovariectomy. Mechanistically, IGF1 promoted ovarian estrogen synthesis, which bound to cardiac ER? to enhance CPT1A transcription, thereby improving mitochondrial fatty acid ?-oxidation and ATP production. Clinical analysis revealed serum IGF1 as an independent protective factor for female HFpEF, positively correlated with estrogen levels, and demonstrated its potential as diagnostic biomarker.

Methods: HFpEF mouse models were established using a 2-Hit protocol: 60% high-fat diet combined with 0.5 g/L N?-nitro-L-arginine methyl ester (L-NAME) in drinking water. Recombinant IGF1 was administered via tail vein injection. Ovariectomy was performed to assess ovarian dependency. Primary follicular granulosa cells and cardiomyocytes were co-cultured for cell-based mechanistic studies. ChIP-qPCR and mass spectrometry were used to characterize ER?-CPT1A interactions and mitochondrial fatty acid oxidation capacity. LC-MS/MS identified downstream fatty acid metabolites of CPT1A, and clinical data were analyzed using statistical methods to evaluate serum IGF1 as a diagnostic marker.

Conclusions: This study establishes a novel ovarian-IGF1-estrogen-ER?-CPT1A signaling axis, whereby serum IGF1 stimulates ovarian estrogen production to activate cardiac ER?-mediated CPT1A transcription, enhancing mitochondrial fatty acid uptake and energy metabolism to inhibit HFpEF progression. Serum IGF1 represents a promising independent protective biomarker with diagnostic utility for HFpEF, particularly in female populations.