Abstract Body (Do not enter title and authors here): Background: Myocardial fibrosis is a key indicator of cardiac remodeling caused by pressure overload, involving a complex interplay of mechanical, inflammatory, and neurohormonal factors. Our recent studies reveal a harmful interaction between visceral adipose tissue (VAT) and the heart during aging, where profibrotic proteins from VAT and plasma contribute to heart fibrosis. We hypothesize that transverse aortic constriction (TAC)-induced pressure overload induces VAT remodeling and VAT profibrotic secretome that aggravates cardiac fibrosis and compromises heart function.
Purpose:
- To determine the interaction between VAT and heart
-To assess the time course of TAC-induced transcriptomic changes in presence or absence of VAT
Methods: We divided wild-type male mice (5-month-old, n=10/group) into four groups: a visceral Lipectomy group and a Sham group two weeks before either a moderate TAC (26G; i.e. gradient between left ventricle and aorta of 30mmHg) or a sham surgery. We sacrificed the mice at 1- and 8-week after TAC. We performed in vivo metabolic tests, echocardiography, and invasive hemodynamics, followed by ex vivo tissue analysis. We subsequently examined cardiac transcriptomic changes in TAC versus control groups, as well as the effect of visceral lipectomy through RNA-seq followed by Partial Least Squares Regression and Over-Representation Pathway Analysis.
Results: TAC-induced cardiac pressure overload initiates a pathological heart-VAT crosstalk stimulating a senescence-like profibrotic (TGFb, Spp1) and proinflammatory secretory phenotype (TNFa, IL6, PAI1) in VAT as early as 1 week after TAC. Importantly, we demonstrate that VAT lipectomy reverses TAC-induced cardiac remodeling and restores normal heart function. Transcriptomic analyses show the powerful effect of TAC on gene expression, notably profibrotic (MMP9, TGFb1, Col1a1) and prohypertrophic genes (Nppa, Nppb) increase. After 1 week, TAC had a stronger effect than lipectomy, while 8 weeks post-TAC, lipectomy could reverse all the transcriptomic changes induced by TAC with a transcriptomic profile of TAC+lipectomy similar to sham group.
Conclusion: This study highlighted the exacerbation by VAT of the detrimental impact of TAC on the heart. Our findings show a dynamic crosstalk between the heart and VAT orchestrated by the secretome of the adipose tissue resulting in transcriptomic and physiological heart changes.