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Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies.

ABSTRACT: Here, we demonstrate that ADAMTS9, a highly conserved versican-degrading protease, is required for correct cardiovascular development and adult homeostasis. Analysis of Adamts9(+/LacZ) adult mice revealed anomalies in the aortic wall, valvulosinus and valve leaflets. Abnormal myocardial projections and 'spongy' myocardium consistent with non-compaction of the left ventricle were also found in Adamts9(+/LacZ) mice. During development, Adamts9 was expressed in derivatives of the Secondary Heart Field, vascular smooth muscle cells in the arterial wall, mesenchymal cells of the valves, and non-myocardial cells of the ventricles, but expression also continued in the adult heart and ascending aorta. Thus, the adult cardiovascular anomalies found in Adamts9(+/LacZ) hearts could result from subtle developmental alterations in extracellular matrix remodeling or defects in adult homeostasis. The valvular and aortic anomalies of Adamts9(+/LacZ) hearts were associated with accumulation of versican and a decrease in cleaved versican relative to WT littermates. These data suggest a potentially important role for ADAMTS9 cleavage of versican, or other, as yet undefined substrates in development and allostasis of cardiovascular extracellular matrix. In addition, these studies identify ADAMTS9 as a potential candidate gene for congenital cardiac anomalies. Mouse models of ADAMTS9 deficiency may be useful to study myxomatous valve degeneration.

SUBMITTER: Kern CB

PROVIDER: S-EPMC2862783 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies.

Kern Christine B CB Wessels Andy A McGarity Jessica J Dixon Laura J LJ Alston Ebony E Argraves W Scott WS Geeting Danielle D Nelson Courtney M CM Menick Donald R DR Apte Suneel S SS

Matrix biology : journal of the International Society for Matrix Biology 20100122 4

Here, we demonstrate that ADAMTS9, a highly conserved versican-degrading protease, is required for correct cardiovascular development and adult homeostasis. Analysis of Adamts9(+/LacZ) adult mice revealed anomalies in the aortic wall, valvulosinus and valve leaflets. Abnormal myocardial projections and 'spongy' myocardium consistent with non-compaction of the left ventricle were also found in Adamts9(+/LacZ) mice. During development, Adamts9 was expressed in derivatives of the Secondary Heart Fi ...[more]

PMID: 20096780

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Project description:ObjectiveOne-staged surgical treatment of aortic coarctation combined with cardiac anomalies is challenging. We aim to evaluate the feasibility of bilateral aortofemoral bypass technique in one-staged surgery treating coractation by comparing surgical outcomes with catheter intervention plus stent (hybrid).MethodsBetween January 2012 and December 2017, 50 patients underwent one-staged surgical procedures to treat coarctation and repair concomitant cardiac anomalies, like aortic root dilatation, cardiac valvular disease and so on. Among them, 30 patients underwent bilateral aortofemoral bypass and 20 patients underwent hybrid procedure to treat coarctation. We retrospectively analyzed the data of these patients and compared the early and late results.ResultsAll the baseline clinical characteristics were comparable between groups except that the mean age of bypass group was 39.5 ± 14.0 years which was older than hybrid group (27.9 ± 8.5 years, P = 0.002). Technical success was achieved in all patients, with no hospital death or other severe complications. Immediately after surgery, in bypass and hybrid group, the mean upper-limb systolic blood pressure decreased from 159.4 to 119.7 mmHg and 148.4 to 111.6 mmHg, the median peak systolic gradient decreased from 68.0 to 10 mmHg and 46.5 to 10 mmHg respectively (P = 0.09). And the mean upper-lower limbs gradient decreased from 21.7 to 5.9 mmHg and 21.0 to 2.7 mmHg respectively (P = 0.104). The mean follow-up time was 76.92 ± 18.7 in bypass group and 85.4 ± 20.6 months in hybrid group. There were 4 late deaths in bypass group (one died of gastrointestinal bleeding, one died of pulmonary embolism and the other two died of heart failure caused by mechanical prosthetic valve dysfunction). The follow-up peak systolic gradient and other blood pressure parameters showed stable and no differences between two groups.ConclusionsThe bilateral aortofemoral bypass surgery is a safe and effective method which can be used in one-staged surgical strategy to treat coarctation complicated by cardiac anomalies and can be an alternative to the hybrid method.

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Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies.

Publications

Reduced versican cleavage due to Adamts9 haploinsufficiency is associated with cardiac and aortic anomalies.

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