Increased calcification by erythrophagocytosis in aortic valvular interstitial cells

Area of Science:

• Cardiovascular Biology
• Pathophysiology of Valvular Heart Disease
• Cellular Mechanisms of Calcification

Background:

• Calcific aortic valve disease (CAVD) is a progressive condition leading to severe aortic stenosis and heart failure.
• Intraleaflet hemorrhage (ILH) is increasingly recognized as a significant promoter of CAVD progression.
• The precise mechanisms by which ILH contributes to valvular calcification remain incompletely understood.

Purpose of the Study:

• To investigate the mechanistic link between intraleaflet hemorrhage (ILH) and the progression of calcific aortic valve disease (CAVD).
• To elucidate how red blood cell (RBC) breakdown within the aortic valve contributes to valvular interstitial cell (VIC) calcification.

Main Methods:

• Morphological analysis was used to identify ILH as iron deposition in aortic valve tissue.
• Human valvular interstitial cells (VICs) were cultured with senescent or fresh red blood cells (RBCs) to simulate ILH conditions.
• The impact of senescent RBCs on VIC calcification and the effect of ferroptosis inhibition were assessed.

Main Results:

• Intraleaflet hemorrhage (ILH) was frequently observed in aortic valves from patients with severe aortic stenosis.
• Valvular interstitial cells (VICs) exhibited erythrophagocytosis of senescent RBCs, leading to intracellular iron accumulation.
• Exposure to senescent RBCs significantly enhanced VIC calcification, an effect mitigated by ferroptosis inhibition.

Conclusions:

• Erythrophagocytosis by VICs, resulting in iron accumulation and ferroptosis, is identified as a key mechanism linking ILH to enhanced valvular calcification.
• This pathway may play a critical role in the pathophysiology of accelerated aortic stenosis progression driven by ILH.
• Targeting ferroptosis presents a potential therapeutic strategy for managing CAVD.