Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

Xin, Hong‐Bo; Senbonmatsu, Takaaki; Cheng, Dong-Sheng; Wang, Yong-Xiao; Copello, Julio A.; Ji, Guangju; Collier, Mei Lin; Deng, Ke-Yu; Jeyakumar, Loice H.; Magnuson, Mark A.; Inagami, Tadashi; Kotlikoff, Michael I.; Fleischer, Sidney

doi:10.1038/416334a

Cited by 264 publications

(224 citation statements)

References 31 publications

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“…Transgenic overexpression of phospholamban, TNF-a, b2AR, NCX showed a gender-related discrepancy in the cardiac phenotype in which the more severe phenotype was observed in males [38][39][40][41]. Similarly, gene disruption of FKBP12.6, phospholamban, and ERa revealed a cardiac phenotype with male preponderance [42][43][44]. Studies with patients hospitalized for acute heart failure in the EuroHeart Failure Survey II revealed that men had DCM more frequently than women [45].…”

Section: Discussionmentioning

confidence: 99%

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Peche

Holak

Burgute

et al. 2012

Cell. Mol. Life Sci.

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Cyclase-associated proteins are highly conserved proteins that have a role in the regulation of actin dynamics. Higher eukaryotes have two isoforms, CAP1 and CAP2. To study the in vivo function of CAP2, we generated mice in which the CAP2 gene was inactivated by a gene-trap approach. Mutant mice showed a decrease in body weight and had a decreased survival rate. Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calciumregulated force development. At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis. We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain. Thus CAP2 is an essential component of the myocardial sarcomere and is essential for physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects.

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Section: Discussionmentioning

confidence: 99%

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Peche

Holak

Burgute

et al. 2012

Cell. Mol. Life Sci.

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“…This may be explained by a protective role of estrogens in the hypertrophic response and the evidence that exposure of cardiac myocytes to androgen results in hypertrophy. 32,33 Furthermore, the HCM phenotype is influenced by sex hormone receptor variants. 34 However, in our study, the sex effect in the probands was less clear, with females tending to be more heavily affected at young age, although one must acknowledge that there was considerable overlap between males and females in this group (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

et al. 2012

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The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P ¼ 0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.

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“…However, there is considerable debate regarding the role of FKBP12 in TGF-␤ signaling, since many members of FKBP are found to be expressed ubiquitously. Therefore, it is still unclear which isoform of FKBP is involved in TGF-␤ signaling in T cells (51)(52)(53)(54). In the absence of TGF-␤1 there could be disequilibria of TGF-␤ type I receptorassociated FKBPs, resulting in leaky Ca 2ϩ release channels.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes

Bommireddy¹,

Saxena²,

Ormsby³

et al. 2003

The Journal of Immunology

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TGF-β1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-β1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-β1-deficient mice. Here we demonstrate that unlike wild-type splenic lymphocytes, those from Tgfb1−/− mice are hyporesponsive to receptor-mediated mitogenic stimulation, as evidenced by diminished proliferation and reduced IL-2 production. However, they have elevated levels of IFN-γ and eventually undergo apoptosis. Receptor-independent stimulation of Tgfb1−/− T cells by PMA plus ionomycin induces IL-2 production and mitogenic response, and it rescues them from anergy. Tgfb1−/− T cells display decreased CD3 expression; increased expression of the activation markers LFA-1, CD69, and CD122; and increased cell size, all of which indicate prior activation. Consistently, mutant CD4+ T cells have elevated intracellular Ca2+ levels. However, upon subsequent stimulation in vitro, increases in Ca2+ levels are less than those in wild-type cells. This is also consistent with the anergic phenotype. Together, these results demonstrate that the ex vivo proliferative hyporesponsiveness of Tgfb1−/− splenic lymphocytes is due to prior in vivo activation of T cells resulting from deregulated intracellular Ca2+ levels.

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Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

Cited by 264 publications

References 31 publications

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

TGF-β1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes

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