T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure

Gröschel, Carina; Sasse, Andre Deeke; Röhrborn, Charlotte; Monecke, Sebastian; Didié, Michael; Elsner, Leslie; Krüse, Vibeke; Bunt, Gertrude; Lichtman, Andrew H.; Toischer, Karl; Zimmermann, Wolfram‐Hubertus; Hasenfuß, Gerd; Dressel, Ralf

doi:10.1038/s41598-017-16147-1

Cited by 32 publications

(34 citation statements)

References 60 publications

(104 reference statements)

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“…For Transverse aortic constriction (TAC) female mice of an age between 8 and 12 weeks were used for experiments. TAC was performed by surgical placement of a suture around the transverse aorta sized to a 26G needle, as described previously ( Gröschel et al., 2017 ). Mice were subjected either to TAC or a sham operation.…”

Section: Methodsmentioning

confidence: 99%

Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia

et al. 2018

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SummaryMitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs, integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin remodeling, upon loss of the cardiolipin acyl transferase tafazzin, decreases HIF-1α signaling in hypoxia. Tafazzin deficiency does not affect posttranslational HIF-1α regulation but rather HIF-1α gene expression, a dysfunction recapitulated in iPSC-derived cardiomyocytes from Barth syndrome patients with tafazzin deficiency. RNA-seq analyses confirmed drastically altered signaling in tafazzin mutant cells. In hypoxia, tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-κB activation and concomitantly HIF-1α gene expression. Tafazzin-deficient mice hearts display reduced HIF-1α levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin remodeling dampens HIF-1α signaling due to a lack of NF-κB activation through reduced mitochondrial ROS production, decreasing HIF-1α transcription.

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Section: Methodsmentioning

confidence: 99%

Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia

et al. 2018

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“…TAC and sham surgery was performed as described previously ( 12 , 16 ). Briefly, the mice received intraperitoneal injections of medetomidin (0.5 mg/kg), midazolam (5 mg/kg), and fentanyl (0.05 mg/kg) for anesthesia.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently demonstrated that T helper cells with specificity for an antigen in cardiomyocytes can contribute to the progression of heart failure after TAC also independently of autoantibodies ( 12 ). For this purpose, cMy-mOVA mice expressing the model antigen ovalbumin (OVA) on cardiomyocytes ( 13 ) were crossed with OT-II mice ( 14 ) expressing a transgenic T cell receptor (TCR) on CD4 + -T cells with specificity for OVA.…”

Section: Introductionmentioning

confidence: 99%

“…In the resulting double-transgenic cMy-mOVA-OT-II mice, progression from hypertrophy to heart failure after TAC was accelerated compared to cMy-mOVA mice. No OVA-specific antibodies were found after TAC but more T cells infiltrated the myocardium of cMy-mOVA-OT-II than cMy-mOVA mice where they could directly contribute to maladaptive cardiac remodeling ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

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CD8+-T Cells With Specificity for a Model Antigen in Cardiomyocytes Can Become Activated After Transverse Aortic Constriction but Do Not Accelerate Progression to Heart Failure

et al. 2018

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Heart failure due to pressure overload is frequently associated with inflammation. In addition to inflammatory responses of the innate immune system, autoimmune reactions of the adaptive immune system appear to be triggered in subgroups of patients with heart failure as demonstrated by the presence of autoantibodies against myocardial antigens. Moreover, T cell-deficient and T cell-depleted mice have been reported to be protected from heart failure induced by transverse aortic constriction (TAC) and we have shown recently that CD4+-helper T cells with specificity for an antigen in cardiomyocytes accelerate TAC-induced heart failure. In this study, we set out to investigate the potential contribution of CD8+-cytotoxic T cells with specificity to a model antigen (ovalbumin, OVA) in cardiomyocytes to pressure overload-induced heart failure. In 78% of cMy-mOVA mice with cardiomyocyte-specific OVA expression, a low-grade OVA-specific cellular cytotoxicity was detected after TAC. Adoptive transfer of OVA-specific CD8+-T cells from T cell receptor transgenic OT-I mice before TAC did not increase the risk of OVA-specific autoimmunity in cMy-mOVA mice. After TAC, again 78% of the mice displayed an OVA-specific cytotoxicity with on average only a three-fold higher killing of OVA-expressing target cells. More CD8+ cells were present after TAC in the myocardium of cMy-mOVA mice with OT-I T cells (on average 17.5/mm2) than in mice that did not receive OVA-specific CD8+-T cells (3.6/mm2). However, the extent of fibrosis was similar in both groups. Functionally, as determined by echocardiography, the adoptive transfer of OVA-specific CD8+-T cells did not significantly accelerate the progression from hypertrophy to heart failure in cMy-mOVA mice. These findings argue therefore against a major impact of cytotoxic T cells with specificity for autoantigens of cardiomyocytes in pressure overload-induced heart failure.

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“…52 When ovalbumin peptide is exclusively expressed on cardiomyocytes, cardiac inflammation is partially restored, suggesting that T-cell activation with ovalbumin peptide can mediate some pathology, but other signals are required to progress to HF. 57 Although IFN-g is profibrotic, IL-10 is antifibrotic, in TAC. 54,58 The mechanisms of immune cell trafficking to the heart in response to cardiac pressure overload are starting to be unveiled.…”

Section: Pressure Overloadeinduced Hfmentioning

confidence: 99%

Heart Inflammation

Carrillo‐Salinas

Ngwenyama

Anastasiou

et al. 2019

The American Journal of Pathology

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T helper cells with specificity for an antigen in cardiomyocytes promote pressure overload-induced progression from hypertrophy to heart failure

Cited by 32 publications

References 60 publications

Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia

Defective Mitochondrial Cardiolipin Remodeling Dampens HIF-1α Expression in Hypoxia

CD8+-T Cells With Specificity for a Model Antigen in Cardiomyocytes Can Become Activated After Transverse Aortic Constriction but Do Not Accelerate Progression to Heart Failure

Heart Inflammation

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