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Therapeutic CCR2 Blockade Prevents Inflammation and Alleviates Myxomatous Valve Disease in Marfan Syndrome.

ABSTRACT: Myxomatous valve disease (MVD) can lead to cardiac dysfunction and heart failure, yet medical therapies are lacking. C-C chemokine receptor type 2 (CCR2)+ immune cell infiltration promotes mitral valve inflammation in a Marfan syndrome (MFS) mouse model. The CCR2 genetic knockout reduces inflammation with downregulated proteases and improved extracellular matrix integrity. Pharmacological inhibition of CCR2+ cell infiltration by RS504393 prevents the initiation and progression of MVD, indicated by restored protease expression, improved extracellular matrix organization, and reduced valve leaflet thickness in MFS mice. Thus, the CCR2 antagonist RS504393 is a promising therapy for the treatment of MVD in MFS.

SUBMITTER: Xu N

PROVIDER: S-EPMC9849467 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Therapeutic CCR2 Blockade Prevents Inflammation and Alleviates Myxomatous Valve Disease in Marfan Syndrome.

Xu Na N Yutzey Katherine E KE

JACC. Basic to translational science 20221012 11

Myxomatous valve disease (MVD) can lead to cardiac dysfunction and heart failure, yet medical therapies are lacking. C-C chemokine receptor type 2 (CCR2)+ immune cell infiltration promotes mitral valve inflammation in a Marfan syndrome (MFS) mouse model. The CCR2 genetic knockout reduces inflammation with downregulated proteases and improved extracellular matrix integrity. Pharmacological inhibition of CCR2+ cell infiltration by RS504393 prevents the initiation and progression of MVD, indicated ...[more]

PMID: 36687269

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Project description:BackgroundMyxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known.MethodsWe examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (Fbn1C1039G/+), gene-edited MFS pigs (FBN1Glu433AsnfsX98/+), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)-tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages (Fbn1C1039G/+;Ccr2RFP/RFP) were generated to determine the requirements of recruited macrophages to MVD progression.ResultsMFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2-), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity.ConclusionsAll together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.

Dataset Information

Therapeutic CCR2 Blockade Prevents Inflammation and Alleviates Myxomatous Valve Disease in Marfan Syndrome.

Publications

Therapeutic CCR2 Blockade Prevents Inflammation and Alleviates Myxomatous Valve Disease in Marfan Syndrome.

Similar Datasets

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