Loss of talin in cardiac fibroblasts results in augmented ventricular cardiomyocyte hypertrophy in response to pressure overload
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE189323 | GEO | 2022/04/27
REPOSITORIES: GEO
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Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
2024-07-15 | PXD053051 | Pride
Project description:Lionheart LincRNA Alleviates Cardiac Systolic Dysfunction under Pressure Overload
| PRJNA644194 | ENA
Project description:Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Klf9 is dysregulated in human and rodent cardiomyopathy. Young adult global Klf9-knockout mice displayed hypertrophic cardiomyopathy that was characterized by depressed systolic function, increased left ventricular mass and pulmonary congestion. Klf9 knockout led to mitochondrial disarray and fragmentation in cardiomyocytes. Biochemical analysis confirmed that mitochondrial respiratory function was impaired in Klf9-knockout cardiomyocytes, with reduced myocardial ATP levels and elevated ROS. Furthermore, cardiac-specific Klf9-deficient mice phenocopied global Klf9-knockout mice, suggesting that cardiac Klf9 is essential for mitochondrial homeostasis and heart function. Moreover, cardiac Klf9 deficiency inhibited mitophagy induced by angiotensin II (ANGII), thereby leading to accumulation of dysfunctional mitochondria and acceleration of heart failure in mice in response to ANGII treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function via promoting mitophagy in mice in response to ANGII treatment. Molecular mechanism studies indicated that Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2 by directly binding to its promoter region, thereby regulating mitochondrial dynamics and mitophagy. Finally, we performed Mfn2 rescue experiments in Klf9-CKO mice and found that AAV-mediated Mfn2 rescue in heart improved cardiac mitochondrial and systolic function in Klf9-CKO mice treated with or without ANGII. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure.
2024-10-03 | GSE278326 | GEO
Project description:Pressure overload-induced cardiac hypertrophy was examined in IL-18 knockout and littermate control mice. Keywords: genetic modification / disease model
2006-07-04 | GSE5129 | GEO
Project description:Left ventricular systolic dysfunction in female NBCe1-B/C-knockout mice
| PRJNA925818 | ENA
Project description:Background: In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods: We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. Results: RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4-hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 vs. RV hypertrophy 334.3±30.65 vs. RV failure 165.4±36.72 pmol/(sec*ml), p<0.0001). Mitochondrial fission protein DRP1 did not change, while MFF decreased and fusion protein OPA1 decreased. In contrast, transcription of electron transport chain genes increased in the left ventricle of RV failure. Conclusion: Pressure overload-induced RV failure is characterized by decreased transcription and activity of electron transport chain complexes and increased oxidative stress which are associated with decreased energy generation. An improved understanding of the complex processes of energy generation could aid in developing novel therapies to mitigate mitochondrial dysfunction and delay the onset of RV failure.
2021-03-18 | GSE152413 | GEO
Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
2024-07-15 | PXD053037 | Pride
Project description:Loss of talin in cardiac fibroblasts results in augmented ventricular cardiomyocyte hypertrophy in response to pressure overload
| PRJNA782559 | ENA
Project description:The genetic background of mice used in this study is mainly C57BL/6J with a small contribution from 129/Sv and DBA/2J strains. Male littermates were received continuous administration of AngII for 7 days at 0.9ug/hour. On day 7 of AngII infusion, the blood pressure of infused mice was (mmHg, mean ± SD) 156 ± 1, while the control littermates remained normotensive (106 ± 9). Keywords: other
2003-10-20 | E-GEOD-606 | biostudies-arrayexpress
Project description:Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)
| PRJNA1047941 | ENA