# Thrombospondin 1 aggravates cardiac remodeling in heart failure with preserved ejection fraction by inhibiting mitophagy

## TL;DR

Thrombospondin 1 worsens heart failure with preserved ejection fraction by blocking the removal of damaged mitochondria, and reducing it improves heart function.

## Contribution

This study identifies Thrombospondin 1 as a novel inhibitor of mitophagy in HFpEF and suggests it as a potential therapeutic target.

## Key findings

- Thrombospondin 1 is elevated in HFpEF myocardium and linked to cardiac remodeling.
- Knocking down Thrombospondin 1 improves diastolic function and reduces fibrosis and inflammation.
- Thrombospondin 1 inhibits mitophagy via the PI3K/Akt/mTOR pathway.

## Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases, but its underlying mechanisms remain unclear. Mitochondrial dysfunction and defective mitophagy are increasingly recognized as central features of HFpEF. Thrombospondin 1 (Thbs1), a matricellular protein involved in cardiovascular remodeling, has not been explored in this context. Here, we show that Thbs1 expression is elevated in HFpEF myocardium and that Thbs1 aggravates cardiac dysfunction by inhibiting mitophagy. In a “two-hit” HFpEF mouse model induced by high-fat diet and L-NAME, AAV9-mediated Thbs1 knockdown improved diastolic function, reduced fibrosis and inflammation, and mitigated PI3K/Akt/mTOR pathway activation revealed by transcriptomic and proteomic profiling. Mechanistically, Thbs1 silencing restored autophagic flux, enhanced mitochondrial clearance, and preserved mitochondrial homeostasis in cardiomyocytes. These findings identify Thbs1 as a key suppressor of mitophagy in HFpEF and a potential therapeutic target for this prevalent condition.

•Thbs1 is upregulated in myocardium of HFpEF mice and correlates with remodeling•Thbs1 knockdown alleviates fibrosis, hypertrophy, and oxidative stress in HFpEF mice•Thbs1 suppresses mitophagy by activating the PI3K/Akt/mTOR signaling pathway•Targeting Thbs1 restores mitochondrial homeostasis and improves diastolic function in HFpEF

Thbs1 is upregulated in myocardium of HFpEF mice and correlates with remodeling

Thbs1 knockdown alleviates fibrosis, hypertrophy, and oxidative stress in HFpEF mice

Thbs1 suppresses mitophagy by activating the PI3K/Akt/mTOR signaling pathway

Targeting Thbs1 restores mitochondrial homeostasis and improves diastolic function in HFpEF

Cell biology; Omics; Model organism