Collagen XIV is important for growth and structural integrity of the myocardium

Abstract

Collagen XIV is a fibril-associated collagen with an interrupted triple helix (FACIT). Previous studies have shown that this collagen type regulates early stages of fibrillogenesis in connective tissues of high mechanical demand. Mice null for Collagen XIV are viable, however formation of the interstitial collagen network is defective in tendons and skin leading to reduced biomechanical function. The assembly of a tightly regulated collagen network is also required in the heart, not only for structural support but also for controlling cellular processes. Collagen XIV is highly expressed in the embryonic heart, notably within the cardiac interstitium of the developing myocardium, however its role has not been elucidated. To test this, we examined cardiac phenotypes in embryonic and adult mice devoid of Collagen XIV. From as early as E11.5, Col14a1−/− mice exhibit significant perturbations in mRNA levels of many other collagen types and remodeling enzymes (MMPs, TIMPs) within the ventricular myocardium. By post natal stages, collagen fibril organization is in disarray and the adult heart displays defects in ventricular morphogenesis. In addition to the extracellular matrix, Col14a1−/− mice exhibit increased cardiomyocyte proliferation at post natal, but not E11.5 stages, leading to increased cell number, yet cell size is decreased by 3 months of age. In contrast to myocytes, the number of cardiac fibroblasts is reduced after birth associated with increased apoptosis. As a result of these molecular and cellular changes during embryonic development and post natal maturation, cardiac function is diminished in Col14a1−/− mice from 3 months of age; associated with dilation in the absence of hypertrophy, and reduced ejection fraction. Further, Col14a1 deficiency leads to a greater increase in left ventricular wall thickening in response to pathological pressure overload compared to wild type animals. Collectively, these studies identify a new role for type XIV collagen in the formation of the cardiac interstitium during embryonic development, and highlight the importance of the collagen network for myocardial cell survival, and function of the working myocardium after birth.

A Comprehensive TALEN-Based Knockout Library for Generating Human-Induced Pluripotent Stem Cell–Based Models for Cardiovascular Diseases

“…We found that the TBX5 was bound to promoter regions of key components of the embryonic provisional matrix, including perlecan (HSPG2), 30 fibronectin (FN1), 31,32 fibulin-1 ( FBLN1 ), 33 collagen XIV ( COL14A3 ), 34 versican ( VCAN ), 35–37 and versican-degrading protease ADMTS9 . 34 These ECM components play essential roles in cardiac development and are indispensable for normal heart development by regulating heart tube segmentation, chamber specification, endocardial cushion formation, interventricular septal formation, and cardiac myocyte differentiation. 38 Taken together, these data suggest that genes encoding embryonic ECM components are direct TBX5 targets and represent potential novel candidate genes associated with HOS and CHD.…”

Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice

“…Additionally, a total of 15 module-5 genes have been implicated in the development of HF and HF-related traits. Of these, six genes are predicted to be cardioprotective, as deficiencies promote cardiac remodeling ( Col14a1 [Tao et al, 2012], Dkk3 [Bao et al, 2015], and Timp1 [Ikonomidis et al, 2005]) or decrease angiogenesis and neovascularization ( Olfml3 [Miljkovic-Licina et al, 2012], Srpx2 [Miljkovic-Licina et al, 2009], and Ptn [Li et al, 2007]). In contrast, six genes are probably maladaptive, as their overexpression leads to increases in cardiac remodeling ( Col6a2 [Grossman et al, 2011], Cx3cl1 [Xuan et al, 2011], Egfr [Messaoudi et al, 2012], Pcolce [Kessler-Icekson et al, 2006], and Tnc [Nishioka et al, 2010]), oxidative stress ( Nox4 ), or fibrosis ( Itga11 [Talior-Volodarsky et al, 2012]) during HF.…”

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

“…6. COL15A1 (IVS12 + 1 G>T, Heterozygous) This splicing variant was identified in a 10-year-old boy who presented with mitral valve prolapse and joints hypermobility, and the mouse phenotype appears compatible (Tao et al 2012). Homozygous) This variant was identified in a 12-year-old boy who presented syndromic corneal opacity, mild intellectual disability and an absent corneal reflex.…”