PhD Candidate Univ. of Minnesota, Twin Cities Minneapolis, Minnesota, United States
Disclosure(s):
Charles Roll: No financial relationships to disclose
Introduction/Rationale: Cardiac valve inflammation accompanies several autoantibody-mediated diseases. Interestingly, this pathology is typically restricted to the higher pressure left side of the heart (mitral and aortic valves), suggesting a link between mechanical stress and inflammation. The K/B.g7 mouse model of autoimmune arthritis and valvular carditis recapitulates key aspects of autoimmune valvular carditis in humans, including attack of the left-sided cardiac valves. We hypothesized that mechanosensing drives this side-specific susceptibility and investigated the role of PIEZO1, a mechanosensitive ion channel, in mediating autoimmune valvular carditis.
Methods: Using the K/B.g7 mouse model, we conditionally deleted PIEZO1 in endothelial cells (Cdh5-Cre), macrophages (Cx3Cr1-Cre), and fibroblasts (Tcf21-Cre). Cdh5 and Tcf21 Cre-mediated deletion were induced via oral tamoxifen gavage at 4 weeks of age, whereas Cx3cr1 Cre-mediated deletion was constitutive. Hearts were harvested from 8-week-old mice. Valve thickness and pathology were quantified via hematoxylin and eosin (H&E) staining of histological sections.
Results: Deletion of PIEZO1 in Tcf21+ fibroblasts significantly reduced valve inflammation and thickening (p=0.0343). In contrast, PIEZO1 deletion in endothelial cells (p=0.7984) or macrophages (p=0.9118) did not attenuate pathology. Preliminary experiments show no significant differences in valve adhesion receptor expression, cellular proliferation, or collagen organization following fibroblast-specific loss of PIEZO1.
Conclusion: These results demonstrate that PIEZO1 expressed by Tcf21+ fibroblasts is a critical contributor to mitral valve inflammation in autoimmune valvular carditis. While specific downstream mechanisms remain to be elucidated, they likely include numerical cell changes, extracellular matrix remodeling, and/or altered intercellular communication. These findings suggest that fibroblast-mediated mechanosensing could underlie the left-sided bias observed in autoimmune valvular carditis.
