Abstract 19920: Cardiac Myosin Binding Protein-C Modulates the Cellular Immune Response to Protect the Heart

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Introduction: Sepsis and inflammation can cause cardiac dysfunction. Cardiac myosin binding protein-C (cMyBP-C), a heart muscle thick filament protein, has 8/11 immunoglobulin domains suggesting a potential role in modulating immune function in the heart.

Hypothesis: cMyBP-C can modulate the immune response to protect the heart.

Methods: Wild type (WT), cMyBP-C(-/-) “KO”, and cMyBP-C(t3SA): cMyBP-C phosphorylation deficient (S273A/S282A/S302A) mice were challenged with 3 intraperitoneal injections of lipopolysaccharide (LPS) over 1 week. Echocardiography and flow cytometric analysis of immune cells (extracted from the heart following isolated heart perfusion) were performed, followed by a proliferation assay to determine the impact of heart leukocytes on splenic proliferative responses.

Results: LPS challenge worsened diastolic dysfunction (increasing E/e’) and hypertrophy (increasing posterior wall thickness “PWTd”) only in KO hearts. Because cMyBP-C(t3SA) hearts exhibit both hypertrophy and diastolic dysfunction similar to KO prior to LPS challenge, but without suffering worsening of dysfunction, the absence of cMyBP-C appears to be the “culprit” for LPS-induced dysfunction. Immunofluorescence showed that LPS increased cardiac myocyte size in KO hearts. Flow cytometry showed that LPS increased leukocytes (CD45+) in WT, but not in KO hearts. The leukocytes expressed surface markers for myeloid derived suppressor cells (Ly6C-low/Ly6G-high of CD11b+). In contrast, LPS increased inflammatory activity of B cells in KO hearts. When autologous heart-extracted leukocytes were co-cultured with syngeneic CD3-activated splenocytes, leukocytes extracted from WT+LPS hearts caused greater proliferation, implying that the presence of cMyBP-C contributes to expansion of protective immune cells in the heart.

Conclusions: The presence of cMyBP-C is associated with cellular immune responses that protects the heart under inflammatory conditions.

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