Transforming growth factor beta signaling in adult cardiovascular diseases and repair

Abstract

The majority of children with congenital heart disease now live into adulthood due to the remarkable surgical and medical advances that have taken place over the past half century. Because of this, adults now represent the largest age group with adult cardiovascular diseases. It includes patients with heart diseases that were not detected or not treated during childhood, those whose defects were surgically corrected but now need revision due to maladaptive responses to the procedure, those with exercise problems and those with age-related degenerative diseases. Because adult cardiovascular diseases in this population are relatively new, they are not well understood. It is therefore necessary to understand the molecular and physiological pathways involved if we are to improve treatments. Since there is a developmental basis to adult cardiovascular disease, transforming growth factor beta (TGFβ) signaling pathways that are essential for proper cardiovascular development may also play critical roles in the homeostatic, repair and stress response processes involved in adult cardiovascular diseases. Consequently, we have chosen to summarize the current information on a subset of TGFβ ligand and receptor genes and related effector genes that, when dysregulated, are known to lead to cardiovascular diseases and adult cardiovascular deficiencies and/or pathologies. A better understanding of the TGFβ signaling network in cardiovascular disease and repair will impact genetic and physiologic investigations of cardiovascular diseases in elderly patients and lead to an improvement in clinical interventions.

Fig. 1

TGFβ signaling pathway and its integration with other major pathways that is likely to be involved in the pathogenesis of cardiovascular diseases in elderly patients. The canonical TGFβ pathway involves SMADs. The non-canonical TGFβ pathways include several SMAD-independent signaling cascades such as calcium-calcineurin and MAPK pathways. The Ang II pathway can interact with TGFβ signaling through both SMAD-dependent and SMAD-independent pathways (see text for details).

Fig. 2

Summary of gene expression patterns of the three TGFβ ligand genes in cardiovascular tissues during embryonic development and adulthood. The data is collected from various in situ hybridization studies (see text for details). Blue, Tgfb1; Brown, Tgfb2; Yellow, Tgfb3. +, presence of gene expression; ++ higher intensity of gene expression; +++, highest level of gene expression; ND, not determined.

Fig. 3

Integrated signaling of TGFβ, Ang II, and MAPK pathways in cardiovascular diseases of elderly patients. The proposed model summarizes the published information about the TGFβ-based therapies and their potential complications for cardiovascular disease-treatment and repair. Black color highlights genes that are found mutated in patients of cardiovascular diseases. Induction or inhibition arrows in solid line indicate the presence of sufficient experimental evidence to support their involvement in cardiovascular disease. The dotted line arrows indicate that there is no direct evidence as yet available and that these require serious investigation.