ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure
Karoline B Rypdal1,2,3, A Olav Melleby4,5, Emma L Robinson6
1Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway. k.b.rypdal@medisin.uio.no.
Insights
ADAMTSL3 protein protects the heart by regulating transforming growth factor-beta (TGFβ) signaling. Loss of ADAMTSL3 worsens heart failure, while its presence inhibits harmful fibroblast activation and collagen production.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Fibrosis Research
Background:
- Heart failure is a leading cause of death, often involving cardiac remodelling due to pressure overload.
- Transforming growth factor-beta (TGFβ) signaling drives cardiac fibroblast (CFB) activation and fibrosis in failing hearts.
- Targeting pathological TGFβ signaling presents a therapeutic opportunity for heart failure.
Purpose of the Study:
- To investigate the role of the secreted glycoprotein ADAMTSL3 in regulating TGFβ signaling within the heart.
- To determine the impact of ADAMTSL3 on cardiac function and remodelling under pressure overload conditions.
Main Methods:
- Utilized Adamtsl3 knock-out mouse models subjected to pressure overload via aortic banding.
- Assessed cardiac function, mortality, TGFβ activity, and cardiac fibroblast activation.
- Examined the effect of ADAMTSL3 overexpression on cultured cardiac fibroblasts, including TGFβ signaling, differentiation, and collagen synthesis.
Main Results:
- Adamtsl3 knock-out mice exhibited exacerbated cardiac dysfunction, dilatation, and increased mortality following pressure overload.
- Hearts from knock-out mice showed elevated TGFβ activity and increased cardiac fibroblast activation.
- Overexpression of ADAMTSL3 in cultured cardiac fibroblasts suppressed TGFβ signaling, myofibroblast differentiation, and collagen production.
Conclusions:
- ADAMTSL3 plays a crucial role in regulating cardiac TGFβ activity and cardiac fibroblast phenotype.
- ADAMTSL3 demonstrates a cardioprotective effect by mitigating pathological cardiac remodelling.
- These findings suggest ADAMTSL3 as a potential therapeutic target for managing heart failure.
Abstract:
Heart failure is a major cause of morbidity and mortality worldwide, and can result from pressure overload, where cardiac remodelling is characterized by cardiomyocyte hypertrophy and death, fibrosis, and inflammation. In failing hearts, transforming growth factor (TGF)β drives cardiac fibroblast (CFB) to myofibroblast differentiation causing excessive extracellular matrix production and cardiac remodelling. New strategies to target pathological TGFβ signalling in heart failure are needed. Here we show that the secreted glycoprotein ADAMTSL3 regulates TGFβ in the heart. We found that Adamtsl3 knock-out mice develop exacerbated cardiac dysfunction and dilatation with increased mortality, and hearts show increased TGFβ activity and CFB activation after pressure overload by aortic banding. Further, ADAMTSL3 overexpression in cultured CFBs inhibits TGFβ signalling, myofibroblast differentiation and collagen synthesis, suggesting a cardioprotective role for ADAMTSL3 by regulating TGFβ activity and CFB phenotype. These results warrant future investigation of the potential beneficial effects of ADAMTSL3 in heart failure.
