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The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [SLAM-IT-seq]

ABSTRACT: Mutations in LMNA, encoding the nuclear lamina protein Lamin A/C, cause malignant dilated cardiomyopathy. A prevailing hypothesis postulates that LMNA mutations cause nuclear envelope ruptures that trigger pathogenic inflammation via the cGAS-STING cytosolic DNA-sensing pathway. Our study suggests that adult mouse cardiomyocytes are unable to activate the cGAS-STING pathway in response to nuclear envelope rupture and proposes that the cGAS-STING pathway is not a pathogenetic component of LMNA-related dilated cardiomyopathy in adult humans. The aim of this project is to investigate the contribution of the cGAS-STING cytosolic DNA-sensing pathway to a mouse model of LMNA-related dilated cardiomyopathy accompanied by nuclear envelope rupture.

ORGANISM(S): Mus musculus

PROVIDER: GSE241589 | GEO | 2024/04/26

REPOSITORIES: GEO

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Project description:Lamin A/C proteins, encoded by the LMNA gene, are intermediate filament proteins of the nuclear lamina, and predominantly expressed in differentiated cells including cardiomyocytes. Mutations in LMNA are associated with laminopathies, congenital diseases affecting muscle and homeostasis. One of the laminopathies associated with a missense mutation (N195K) in the A-type lamins results in dilated cardiomyopathy (DCM) with arrhythmias and sudden death. However it is unknown how the mutation in this LMNA gene contributes to the mechanism of arrhythmia and sudden death. To investigate this a mouse line expressing the Lmna-N195K (LmnaN195K/N195K) was used. Mutant mice demonstrated reduced fractional shortening, LV mass, wall thickness and dilated cardiomyopathy by echocardiography at 6 weeks consistent with human DCM, and died at an early age (6-7 weeks). Comparative cDNA microarray analysis from LmnaN195K/N195K and the wild type (WT) control ventricles at 6 weeks age revealed significant alterations in the expression of ion channels, transporter proteins, caveolins and associated proteins such as MAP kinases. Transmission electron microscopy analysis showed structural alterations of the ventricular myocytes with increase in number of caveolae. Quantitative Western blot analysis confirmed reduced expression for Cavβ (2 fold) subunits of the L-type Ca2+ channel. In contrast the expression levels of Cav3 (2.5 fold) was significantly increased. To investigate the functional impact of Lmna N195K on the ICa,L, we transiently expressed either the WT LMNA+GFP, Lmna N195K+GFP or GFP (control) in isolated neonatal mouse ventricular myocytes and performed whole cell patch clamp analysis. Transient expression of Lmna N195K significantly reduced (58 %) peak ICa,L (-6.0 ± 2 pA/pF, n=9) compared to GFP control (-14 ± 2 pA/pF, n=8). Expression of WT LMNA did not affect the ICa,L (-14.2 ± 2.5 pA/pF, n=8) compared to control. Conclusion: We conclude that Lmna N195K mutation results in reduced expression of ion channels and scaffolding proteins in the left ventricle with a significant reduction in peak ICa,L in ventricular myocytes and these may contribute to the mechanism of arrhythmia and dilated cardiomyopathy. 6 samples

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The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [SLAM-IT-seq]

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