Key result
FBN1 deficiency reduces Cav1.2 expression via TGF-β1, inhibiting aortic smooth muscle cell proliferation in Marfan syndrome.
Why the study?
The molecular mechanism underlying Marfan syndrome remains poorly understood, prompting an exploration into how the L-type calcium channel (CaV1.2) modulates disease progression.
FBN1 deficiency in Marfan syndrome decreases Cav1.2 expression via TGF-β1, inhibiting vascular smooth muscle cell proliferation and suggesting Cav1.2 as a potential therapeutic target.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for Cav1.2 targeting in Marfan aortopathy; leaves open clinical translation pending human studies.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutation in fibrillin-1 (FBN1). However, the molecular mechanism underlying MFS remains poorly understood. The study aimed to explore how the L-type calcium channel (CaV1.2) modulates disease progression of MFS and to identify a potential effective target for attenuating MFS. KEGG enrichment analysis showed that the calcium signaling pathway gene set was significantly enriched. We demonstrated that FBN1 deficiency exhibited inhibition on both the expression of Cav1.2 and proliferation of vascular smooth muscle cells (VSMCs). Then, we examined whether FBN1 mediates Cav1.2 via regulating TGF-β1. Higher levels of TGF-β1 were observed in the serum and aortic tissues from patients with MFS. TGF-β1 modulated Cav1.2 expression in a concentration-dependent manner. We evaluated the role of Cav1.2 in MFS by small interfering RNA and Cav1.2 agonist Bay K8644. The effect of Cav1.2 on cell proliferation was dependent on c-Fos activity. These results demonstrated FBN1 deficiency decreased the expression levels of Cav1.2 via regulation of TGF-β1, and downregulation of Cav1.2 inhibited cell proliferation of human aortic smooth muscle cells (HASMCs) in MFS patients. These findings suggest that Cav1.2 may be an appealing therapeutic target for MFS.
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Lin et al. (2023) studied Marfan syndrome. Cav1.2 agonist Bay K8644 and small interfering RNA was evaluated on Cav1.2 expression and cell proliferation. FBN1 deficiency decreased Cav1.2 expression via TGF-β1 regulation, and downregulation of Cav1.2 inhibited cell proliferation of human aortic smooth muscle cells in Marfan syndrome patients.
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