Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus

Raaz, Uwe; Schellinger, Isabel N.; Chernogubova, Ekaterina; Warnecke, Christina; Kayama, Yosuke; Penov, Kiril; Hennigs, Jan K.; Salomons, Florian A.; Eken, Suzanne M; Emrich, Fabian; Zheng, Wei; Adam, Matti; Jagger, Ann; Nakagami, Futoshi; Toh, Ryuji; Toyama, Kensuke; Deng, Alicia; Buerke, Michael; Maegdefessel, Lars; Hasenfuß, Gerd; Spin, Joshua M.; Tsao, Philip S.

doi:10.1161/circresaha.115.306341

Cited by 95 publications

(77 citation statements)

References 52 publications

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“…Passive aortic stiffness largely depends on the matrix composition within the vascular medial layer 46 . Masson’s trichrome staining showed that collagen deposition (blue) was increased in the medial layer of the aortas in KL +/− mice, and this effect was abolished by SRT1720 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of SIRT1 Attenuates Klotho Deficiency–Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity

et al. 2016

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Arterial stiffness is an independent risk factor for stroke and myocardial infarction. This study was designed to investigate the role of SIRT1, an important deacetylase, and its relationship with Klotho, a kidney-derived aging-suppressor protein, in the pathogenesis of arterial stiffness and hypertension. We found that the serum level of Klotho was decreased by nearly 45% in patients with arterial stiffness and hypertension. Interestingly, Klotho haplodeficiency caused arterial stiffening and hypertension, as evidenced by significant increases in pulse wave velocity (PWV) and blood pressure (BP) in Klotho-haplodeficient (KL+/−) mice. Notably, the expression and activity of SIRT1 were decreased significantly in aortic endothelial and smooth muscle cells in KL+/− mice, suggesting that Klotho deficiency downregulates SIRT1. Treatment with SRT1720 (15 mg/kg/day, IP), a specific SIRT1 activator, abolished Klotho deficiency-induced arterial stiffness and hypertension in KL+/− mice. Klotho deficiency was associated with significant decreases in activities of AMP-activated protein kinase alpha (AMPKα) and endothelial nitric oxide synthase (eNOS) in aortas, which were abolished by SRT1720. Furthermore, Klotho deficiency upregulated NADPH oxidase activity and superoxide production, increased collagen expression, and enhanced elastin fragmentation in the media of aortas. These Klotho deficiency-associated changes were blocked by SRT1720. In conclusion, this study provides the first evidence that Klotho deficiency downregulates SIRT1 activity in arterial endothelial and smooth muscle cells. Pharmacological activation of SIRT1 may be an effective therapeutic strategy for arterial stiffness and hypertension.

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Section: Resultsmentioning

confidence: 99%

Activation of SIRT1 Attenuates Klotho Deficiency–Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity

et al. 2016

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“…Runt-related transcription factor 1 ( Runx1 , 4.8-fold, P = 4 × 10 −17 ) controls TGFβ-dependent myofibroblast differentiation (12). The related molecule, Runx2 (4.3-fold, P = 2 × 10 −9 ), is a known regulator of collagen type-1 gene expression and was recently identified as a key mediator of vascular fibrosis (13). PU.1 ( Sfpi1/Spi1 , 3.3-fold, P = 3 × 10 −11 ) is a master transcription factor that regulates the cell-specific response to TGFβ signaling (14).…”

Section: Resultsmentioning

confidence: 99%

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

et al. 2016

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Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10−4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10−33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.

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“…Overexpression of Slug alone did not increased AVIC calcification as well. Since Runx2 is the key transcription factor during early osteoblastic differentiation stage and the degree of calcium deposition at the late stage is not determined by Runx2 (34,35) which elucidates the knockdown of Slug inhibits warfarin-induced pAVIC calcification and overexpression of Slug failed to increase pAVIC calcification. In the current study, we found that p53 not only promoted Slug transcription, but also increased the levels of histone acetyltransferases p300 and CBP, and resulted in increased histone H3 and H4 acetylation.…”

Section: Discussionmentioning

confidence: 96%

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Gao¹,

Ji²,

Lü³

et al. 2018

Journal of Biological Chemistry

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The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), while the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participating in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification.Immunostaining, quantitative PCR and western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. TUNEL staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to lowlevel increase of p53 mRNA and protein both in pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis, but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNAmediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.The tumor suppressor p53 plays important roles in cell cycle regulation, apoptosis, and DNA p53 and aortic valve interstitial cell calcification 2 damage (1), as well as in osteoblastic differentiation and bone development. Deletion of the p53 inhibitor MDM2 in osteoblast lineage cells leads to increased p53 production and suppression of bone organogenesis and homeostasis, whereas deletion of p53 accelerates osteoblast cell differentiation and bone formation (2,3). In addition, using p53 knockout mice with chronic kidney disease, Li, KL, et al. showed that p53 negatively regulates osteogenic differentiation of vascular smooth muscle cells and aortic calcification suggesting the p53 is involved in pathological tissue calcification (4).The vitamin K antagonist, warfarin, is the most frequently used oral anti-coagulant to treat thromboprophylaxis in the presence of atrial fibrillation or a mechanical prosthetic heart valve. Recently, human and animal studies have implicated warfarin use with vascular and valvular calcification. Long-term warfarin treatment impairs vitamin K-dependent modification of many proteins, including matrix gla protein (MGP), inhibits the bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein...

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Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus

Cited by 95 publications

References 52 publications

Activation of SIRT1 Attenuates Klotho Deficiency–Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity

Activation of SIRT1 Attenuates Klotho Deficiency–Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

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