Genetic Manipulation of Periostin Expression in the Heart Does Not Affect Myocyte Content, Cell Cycle Activity, or Cardiac Repair

Abstract

Abstract-Following a pathological insult, the adult mammalian heart undergoes hypertrophic growth and remodeling of the extracellular matrix. Although a small subpopulation of cardiomyocytes can reenter the cell cycle following cardiac injury, the myocardium is largely thought to be incapable of significant regeneration. Periostin, an extracellular matrix protein, has recently been proposed to induce reentry of differentiated cardiomyocytes back into the cell cycle and promote meaningful repair following myocardial infarction. Here, we show that although periostin is induced in the heart following injury, it does not stimulate DNA synthesis, mitosis, or cytokinesis of cardiomyocytes in vitro or in vivo.Mice lacking the gene encoding periostin and mice with inducible overexpression of full-length periostin were analyzed at baseline and after myocardial infarction. There was no difference in heart size or a change in cardiomyocyte number in either periostin transgenic or gene-targeted mice at baseline. Quantification of proliferating myocytes in the periinfarct area showed no difference between periostin-overexpressing and -null mice compared with strain-matched controls. In support of these observations, neither overexpression of periostin in cell culture, via an adenoviral vector, nor stimulation with recombinant protein induced DNA synthesis, mitosis, or cytokinesis. Periostin is a regulator of cardiac remodeling and hypertrophy and may be a reasonable pharmacological target to mitigate heart failure, but manipulation of this protein appears to have no obvious effect on myocardial regeneration. (Circ Res. 2009;104:e1-e7.)

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

“…These observations are superficially in direct opposition to a previous report in which direct application of a truncated version of periostin protein onto infarcted rodent hearts led to increased healing of the injury by induction of regeneration and cell cycle reentry of cardiomyocytes (25). However, a follow-up to that study found that overexpression of fulllength periostin in vitro and in vivo did not alter the regeneration ability of the cardiomyocytes (26). Furthermore, periostin-overexpressing hearts (full-length protein) showed either baseline pathology or an increase in long-term fibrosis or hypertrophy, or worsening function with disease stimulation (16,27).…”

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

“…Results from these independent methodologies were concordant, but as expected, absolute numbers of Ki67 antigen-labeled cells were consistently lower than those of BrdU-labeled cells. As in other studies (26,27), we found no evidence for myocyte proliferation; BrdU and Ki67 antibodies labeled only non-myocyte cells.…”

Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents

“…Therefore, we assume that the activation of MMPs mediates, at least in part, the effects of periostin on collagen fibrillogenesis and angiogenesis. A recent study has indicated that periostin is induced during LV remodeling after cardiac injury without affecting cardiac fibroblast proliferation (35). Interestingly, we also found that periostin was reexpressed during cardiac valve degeneration without affecting VIC proliferation, which suggests that it regulates cardiac pathologic remodeling via common biological mechanisms, including those that involve MMPs.…”

“…In addition to the periosteum and periodontal ligament, periostin is expressed in cancer cells, vascular smooth muscle cells, fibroblasts, and wound-site blood vessels and participates in tumor angiogenesis, metastasis, and cell migration (28)(29)(30)(31). In the heart, periostin is physiologically expressed in embryonic cardiac valves, while it is reexpressed abundantly in adult LV after pressure overload or myocardial infarction (32)(33)(34)(35)(36)(37). Although heart size and cardiomyocyte number are unchanged at baseline in Postn -/-mice, LV remodeling and hypertrophy are attenuated without apparently affecting the proliferation of cardiomyocytes and cardiac fibroblasts, which suggests crucial effects of periostin on LV fibrosis and hypertrophy after cardiac insult (34,35).…”

“…In the heart, periostin is physiologically expressed in embryonic cardiac valves, while it is reexpressed abundantly in adult LV after pressure overload or myocardial infarction (32)(33)(34)(35)(36)(37). Although heart size and cardiomyocyte number are unchanged at baseline in Postn -/-mice, LV remodeling and hypertrophy are attenuated without apparently affecting the proliferation of cardiomyocytes and cardiac fibroblasts, which suggests crucial effects of periostin on LV fibrosis and hypertrophy after cardiac insult (34,35). Previous studies have clearly demonstrated the physiologic role of periostin in the cardiac valve and its critical involvement in cardiac valve maturation during development (38,39).…”