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Tenascin C protects aorta from acute dissection in mice.

ABSTRACT: Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaCl? caused stiffening of abdominal aorta, which augmented the hemodynamic stress and TNC induction in suprarenal aorta by angiotensin II infusion. Deletion of Tnc gene rendered mice susceptible to AAD development upon the aortic stress, which was accompanied by impaired TGF? signaling, insufficient induction of extracellular matrix proteins and exaggerated proinflammatory response. Thus, TNC works as a stress-evoked molecular damper to maintain the aortic integrity under the acute stress.

SUBMITTER: Kimura T

PROVIDER: S-EPMC3920275 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Tenascin C protects aorta from acute dissection in mice.

Kimura Taizo T Shiraishi Kozoh K Furusho Aya A Ito Sohei S Hirakata Saki S Nishida Norifumi N Yoshimura Koichi K Imanaka-Yoshida Kyoko K Yoshida Toshimichi T Ikeda Yasuhiro Y Miyamoto Takanobu T Ueno Takafumi T Hamano Kimikazu K Hiroe Michiaki M Aonuma Kazutaka K Matsuzaki Masunori M Imaizumi Tsutomu T Aoki Hiroki H

Scientific reports 20140211

Acute aortic dissection (AAD) is caused by the disruption of intimomedial layer of the aortic walls, which is immediately life-threatening. Although recent studies indicate the importance of proinflammatory response in pathogenesis of AAD, the mechanism to keep the destructive inflammatory response in check is unknown. Here, we report that induction of tenascin-C (TNC) is a stress-evoked protective mechanism against the acute hemodynamic and humoral stress in aorta. Periaortic application of CaC ...[more]

PMID: 24514259

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Project description:Acute aortic dissection (AAD) is one of the major aortic diseases that occurs without a preceding symptom and often results in sudden death. Despite the recent advances in cardiovascular medicine, AAD remains a serious problem because its molecular pathogenesis is largely unknown. In this paper, we report our serendipitous discovery that stress-induced expression of tenascin C (TNC), a member of matricellular proteins, is the protection mechanism of aorta to prevent AAD. The aortic wall stress imposed by the aortic stiffening and the angiotensin II infusion caused the strong induction of TNC in wild type mouse aorta without gross morphological changes. While TNC knockout mice at the baseline showed no morphological, histological or biomechanical abnormalities of aorta, deletion of TNC gene rendered the aorta susceptible to AAD upon the aortic stress. The stressed TNC-null aorta showed the loss of the tensile strength due to the insufficient expression of extracellular matrix proteins and the exaggerated proinflammatory response before the onset of AAD. Therefore, TNC works as a stress-activated molecular damper both by reinforcing the tensile strength and by limiting the excessive proinflammatory response in aorta. Thus far, the molecular event that leads to the AAD development has been unclear because of the unpredictable nature of the AAD onset. This study sheds light on the previously unrecognized tissue protection mechanism that converts the potentially harmful stress response into the active reinforcement of the aorta, of which failure leads to the development of AAD. Although TNC is expressed in various tissues upon the mechanical and proinflammatory stimuli, its role has long been a mystery. Our data uncovered the adaptive role of TNC in aorta that must be resilient to the continuous hemodynamic and humoral stress for lifetime. We used periaortic application of 0.5 M CaCl2 to the infrarenal aorta or either wild type (WT) or tenascin C knockout (TNC-KO) mice to create the mouse model for stiffened aorta and infused the mice with AngII (1 µg/min/kg) for 1 week to apply the pathological stress on aorta (Ca+AngII). Mice were then killed with an overdose of pentobarbital to obtain the tissue samples. The suprarenal aortic samples, from the level of right renal artery to 10 mm above the right renal artery, and infrarenal aortic samples, from the level of left renal artery to 10 mm below the left renal artery, were collected and kept in RNAlater (Qiagen) until the extraction of total RNA using RNeasy (Qiagen). We obtained the RNA samples from 8 mice with Ca+AngII treatment and 5 mice without Ca+AngII treatment for each genotype. We pooled the RNA samples with the identical experimental condition to perform the transcriptome analysis using Mouse Genome 430 2.0 (Affymetrix). We obtained suprarenal aortic smooth muscle cells (ASMCs) from TNC-KO mice by enzymatic dispersion and cultured them in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum. We cultured TNC-KO ASMCs in the presence or absence of exogenous TNC (10 µg/mL) and stimulated the cells with 10 ng/mL TNF-alpha for 24 h before obtaining total RNA using RNeasy. We used 3 independent ASMC cultures without the exogenous TNC and 4 independent cultures with the exogenous TNC. We hybridized each of the RNA samples individually to Mouse Genome 430 2.0 Array (Affymetrix).

Project description:ObjectiveThe study objective was to evaluate the progression of dissected distal aorta in patients with acute type A aortic dissection with malperfusion syndrome treated with endovascular fenestration/stenting and delayed open aortic repair.MethodsFrom 1996 to 2021, 927 patients presented with acute type A aortic dissection. Of these, 534 had DeBakey I dissection with no malperfusion syndrome and underwent emergency open aortic repair (no malperfusion syndrome group), whereas 97 patients with malperfusion syndrome underwent fenestration/stenting and delayed open aortic repair (malperfusion syndrome group). Sixty-three patients with malperfusion syndrome treated with fenestration/stenting were excluded due to no open aortic repair, including death from organ failure (n = 31), death from aortic rupture (n = 16), and discharged alive (n = 16).ResultsCompared with the no malperfusion syndrome group, the malperfusion syndrome group had more patients with acute renal failure (60% vs 4.3%, P < .001). Both groups had similar aortic root and arch procedures. Postoperatively, the malperfusion syndrome group had similar operative mortality (5.2% vs 7.9%, P = .35) and permanent dialysis (4.7% vs 2.9%, P = .50), but more new-onset dialysis (22% vs 7.7%, P < .001) and prolonged ventilation (72% vs 49%, P < .001). The growth rate of the aortic arch (0.38 vs 0.35 mm/year, P = .81) was similar between the malperfusion syndrome and no malperfusion syndrome groups. The descending thoracic aorta growth rate (1.03 vs 0.68 mm/year, P = .001) and abdominal aorta growth rate (0.76 vs 0.59 mm/year, P = .02) were significantly higher in the malperfusion syndrome group. The cumulative incidence of reoperation over 10 years (18% vs 18%, P = .81) and 15-year survival outcome (50% vs 48%, P = .43) were similar between the malperfusion syndrome and no malperfusion syndrome groups.ConclusionsEndovascular fenestration/stenting followed by delayed open aortic repair was a valid approach for patients with malperfusion syndrome.

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Tenascin C protects aorta from acute dissection in mice.

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Tenascin C protects aorta from acute dissection in mice.

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