ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice

Kouzu, Hidemichi; Tatekoshi, Yuki; Chang, Hsiang Chun; Shapiro, Jason S.; McGee, W Ambrose; Jesus, Adam De; Ben-Sahra, Issam; Arany, Zoltàn; Leor, Jonathan; Chen, Chunlei; Blackshear, Perry J.; Ardehali, Hossein

doi:10.1172/jci154491

Cited by 9 publications

(6 citation statements)

References 68 publications

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“…57,58 Likewise, the overexpression of a negative regulator of Mdm2 mRNA stability, ZFP36L2, was found to facilitate the development of peripartum cardiomyopathy secondary to increased cardiomyocyte p53 activity leading to a reduction of mTorc1. 59 The divergent phenotypic responses in models with partial versus complete ablation of MDM2 is at least somewhat explained by these divergent p53 responses. However, the type and timing of the pathogenic stimulus may also be an important contributor.…”

Section: Discussionmentioning

confidence: 99%

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy

Shridhar,

Glennon,

Pal

et al. 2023

Circulation

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BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein 3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

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Section: Discussionmentioning

confidence: 99%

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy

Shridhar,

Glennon,

Pal

et al. 2023

Circulation

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“…1 It has been proposed that this abnormal growth pattern is related to fetal exposure to high levels of maternal progesterone, followed by its abrupt removal at birth. 31,32 Considering this, it is not surprising that guinea pigs are the only reported rodent species to spontaneously develop CRs, as they have a markedly longer gestational period (59-72 days) than mice (19-21 days), rats (21-23 days), or hamsters (16-22 days).…”

Section: Discussionmentioning

confidence: 99%

Cardiac Rhabdomyoma in Four Göttingen Minipigs

et al. 2023

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Göttingen minipigs are increasingly used as an alternative large animal model in nonclinical toxicology studies, and proliferative lesions in this species are rare. Here, we report four cases of cardiac rhabdomyoma in Göttingen minipigs, an incidental and benign mass in the heart. Three cases lacked gross observations and had a microscopic nodule in either the left ventricle or interventricular septum. The last case had a large, firm, raised nodule on a left ventricular papillary muscle noted at necropsy, with additional microscopic intramural masses in the left ventricular wall. In all cases, microscopic evaluation revealed well-circumscribed, expansile nodules composed of bundles of large, highly vacuolated, ovoid to polygonal cells with variable cytoplasmic processes radiating from a centrally located nucleus. Cells displayed patchy accumulation of intracytoplasmic, PAS-positive material and haphazardly arranged cytoplasmic cross-striations. There was no evidence of cardiac insufficiency or other data to suggest the masses were clinically meaningful. Cardiac rhabdomyomas have been reported in meat-hybrid swine, with a breed predisposition in red wattle. This lesion is well established in guinea pigs, but documentation in other laboratory species used in toxicologic studies is limited to two beagle dogs. To our knowledge, this is the first report of spontaneous cardiac rhabdomyoma in Göttingen minipigs.

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“…The heart requires precise control of mTORC1. Hyperactivation of mTORC1 can increase the chance of postpartum cardiac hypertrophy [79]. As a regulator of mTORC1 activity, SESN2 is necessary to keep mTORC1 levels within control to prevent hypertrophy after birth.…”

Section: Cardiac Hypertrophy and Heart Failurementioning

confidence: 99%

“…As a regulator of mTORC1 activity, SESN2 is necessary to keep mTORC1 levels within control to prevent hypertrophy after birth. An RNA-binding protein (RBP), Zinc finger protein 36 like 2 (ZFP36L2) was found to inhibit mTORC1 to prevent hypertrophy in a p53-dependent manner by increasing the decay of MDM2 mRNA and increasing the expression of SESN2 [79]. The stabilization of p53 by chemical stabilizers could be used as a therapeutic strategy to prevent the hyperactivity of mTORC1 [80].…”

Section: Cardiac Hypertrophy and Heart Failurementioning

confidence: 99%

Sestrin2 as a Protective Shield against Cardiovascular Disease

Zahid

Abdelsalam

Raïq

et al. 2023

IJMS

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A timely and adequate response to stress is inherently present in each cell and is important for maintaining the proper functioning of the cell in changing intracellular and extracellular environments. Disruptions in the functioning or coordination of defense mechanisms against cellular stress can reduce the tolerance of cells to stress and lead to the development of various pathologies. Aging also reduces the effectiveness of these defense mechanisms and results in the accumulation of cellular lesions leading to senescence or death of the cells. Endothelial cells and cardiomyocytes are particularly exposed to changing environments. Pathologies related to metabolism and dynamics of caloric intake, hemodynamics, and oxygenation, such as diabetes, hypertension, and atherosclerosis, can overwhelm endothelial cells and cardiomyocytes with cellular stress to produce cardiovascular disease. The ability to cope with stress depends on the expression of endogenous stress-inducible molecules. Sestrin2 (SESN2) is an evolutionary conserved stress-inducible cytoprotective protein whose expression is increased in response to and defend against different types of cellular stress. SESN2 fights back the stress by increasing the supply of antioxidants, temporarily holding the stressful anabolic reactions, and increasing autophagy while maintaining the growth factor and insulin signaling. If the stress and the damage are beyond repair, SESN2 can serve as a safety valve to signal apoptosis. The expression of SESN2 decreases with age and its levels are associated with cardiovascular disease and many age-related pathologies. Maintaining sufficient levels or activity of SESN2 can in principle prevent the cardiovascular system from aging and disease.

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ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice

Cited by 9 publications

References 68 publications

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy

Cardiac Rhabdomyoma in Four Göttingen Minipigs

Sestrin2 as a Protective Shield against Cardiovascular Disease

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