Complementary Models of Cardiometabolic Stress Reveal Conserved Molecular Programs Driving Cardiac Remodeling
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Cardiometabolic diseases frequently involve concurrent cardiovascular and hepatic dysfunction, yet the conserved molecular mechanisms underlying these systemic responses remain poorly defined.
Objectives
To identify conserved molecular responses across complementary manifestations of cardiometabolic stress and determine whether integrated multi-organ analyses reveal therapeutically actionable targets for heart failure.
Methods
Cardiac functional phenotyping, hepatic injury profiling, and bulk RNA sequencing were performed across three complementary mouse models representing distinct manifestations of cardiometabolic stress: high-fat diet plus L-NAME (HFD+LN)-induced heart failure with preserved ejection fraction (HFpEF; cardiovascular disease), Western diet (WD)-induced obesity (systemic metabolic stress), and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced steatotic liver disease (hepatic metabolic stress). Comparative transcriptomic analyses distinguished organ-specific responses from conserved molecular signatures.
Results
Each model produced distinct systemic, hepatic, and cardiac phenotypes accompanied by divergent transcriptional responses within individual organs. Cross-model and cross-organ integration identified a limited set of conserved molecular responses to cardiometabolic stress, with Serpine1 , encoding plasminogen activator inhibitor-1 (PAI-1), emerging as a highly conserved candidate that exhibited preferential induction in the heart. Pharmacologic inhibition of PAI-1 significantly improved cardiac function and attenuated adverse remodeling in established HFpEF, whereas hepatic pathology was comparatively less affected, indicating differential organ-specific dependence on this pathway.
Conclusions
Integrated analyses across complementary manifestations of cardiometabolic stress identified conserved molecular signatures that transcend individual disease models and organs. These findings establish a comparative framework for discovering cardiovascular therapeutic targets and identify PAI-1 as a promising mediator of cardiac remodeling in HFpEF.
