PDGF-D activation by macrophage-derived uPA promotes AngII-induced cardiac remodeling in obese mice.
Yu-Wen ChengZe-Bei ZhangBei-Di LanJing-Rong LinXiao-Hui ChenLing-Ran KongLian XuCheng-Chao RuanPing-Jin GaoPublished in: The Journal of experimental medicine (2021)
Obesity-induced secretory disorder of adipose tissue-derived factors is important for cardiac damage. However, whether platelet-derived growth factor-D (PDGF-D), a newly identified adipokine, regulates cardiac remodeling in angiotensin II (AngII)-infused obese mice is unclear. Here, we found obesity induced PDGF-D expression in adipose tissue as well as more severe cardiac remodeling compared with control lean mice after AngII infusion. Adipocyte-specific PDGF-D knockout attenuated hypertensive cardiac remodeling in obese mice. Consistently, adipocyte-specific PDGF-D overexpression transgenic mice (PA-Tg) showed exacerbated cardiac remodeling after AngII infusion without high-fat diet treatment. Mechanistic studies indicated that AngII-stimulated macrophages produce urokinase plasminogen activator (uPA) that activates PDGF-D by splicing full-length PDGF-D into the active PDGF-DD. Moreover, bone marrow-specific uPA knockdown decreased active PDGF-DD levels in the heart and improved cardiac remodeling in HFD hypertensive mice. Together, our data provide for the first time a new interaction pattern between macrophage and adipocyte: that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice.
Keyphrases
- adipose tissue
- insulin resistance
- high fat diet
- vascular smooth muscle cells
- smooth muscle
- angiotensin ii
- left ventricular
- high fat diet induced
- bone marrow
- metabolic syndrome
- growth factor
- high glucose
- type diabetes
- blood pressure
- diabetic rats
- drug induced
- heart failure
- oxidative stress
- skeletal muscle
- cell proliferation
- atrial fibrillation
- transcription factor
- physical activity
- angiotensin converting enzyme
- binding protein
- bone mineral density
- big data