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Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA
Marie Kervella1,2, Charlotta S Behrens3,4, Cécile Peccate1
1Institute of Myology, Center of Research in Myology, Sorbonne University, Inserm, Paris, France (M.K., C.P., Z.G., F.G., A.F., A.M.).
Insights
LMNA-associated dilated cardiomyopathy involves heart dysfunction and fibrosis. Inhibiting Loxl2 with Simtuzumab effectively prevented cardiac issues in a study using patient-derived cells and a mouse model.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Genetic Medicine
Background:
- LMNA mutations cause severe dilated cardiomyopathy (DCM) with arrhythmias, contractile dysfunction, and fibrosis.
- Impaired left ventricular function and heart failure risk are key features of LMNA-DCM.
- Limited understanding of pathogenesis has hindered therapeutic development for LMNA-DCM.
Purpose of the Study:
- Investigate functional and molecular abnormalities in LMNA-associated dilated cardiomyopathy.
- Utilize patient-derived human induced pluripotent stem cells (hiPSCs) and a murine model with a specific LMNA mutation (c.665A>C, p.His222Pro).
Main Methods:
- Generated and analyzed patient-derived cardiomyocytes and engineered heart tissues (EHTs).
- Assessed cellular function, nuclear morphology, chromosome organization, and gene expression.
- Conducted transcriptomic analysis to identify key molecular pathways.
- Utilized a murine model carrying the same LMNA mutation.
Main Results:
- LMNA-mutated cardiomyocytes showed diastolic calcium elevation and hypocontractility.
- Nuclear shape abnormalities and disrupted chromosome organization were observed.
- Transcriptomic analysis revealed extracellular matrix remodeling and Loxl2 upregulation.
- Simtuzumab treatment prevented cardiac dysfunction and fibrosis in the murine model.
Conclusions:
- Loxl2 plays a critical role in the pathogenesis of LMNA-associated dilated cardiomyopathy.
- Loxl2 inhibition is a potential therapeutic strategy for preserving cardiac function.
- Targeting Loxl2 offers a promising avenue for treating LMNA-DCM.
Background:
Dilated cardiomyopathy caused by LMNA mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. Although the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies.
Methods:
Here, we employed human induced pluripotent stem cells (hiPSCs) derived from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving dilated cardiomyopathy.
Results:
We demonstrated that LMNA patient-derived cardiomyocytes and engineered heart tissues exhibited elevated diastolic calcium levels and reduced sensitivity to external calcium, respectively, as well as hypocontractility. These cells also displayed nuclear shape abnormalities in 2-dimensional and 3-dimensional, a hallmark of LMNA-associated dilated cardiomyopathy, associated with disrupted chromosome spatial organization and altered gene expression profiles. Transcriptomic analysis revealed dysregulation of extracellular matrix remodeling and significant upregulation of Loxl2 in mutated hiPSC-cardiomyocytes, hiPSC-engineered heart tissues, and mice. Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac dysfunction and fibrosis in vivo.
Conclusions:
Taken together, our findings underscore the crucial role of Loxl2 as a therapeutic target and suggest that its inhibition could be a promising strategy to preserve cardiac function in LMNA-associated dilated cardiomyopathy.
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