Molecular mechanisms of oxidative injury and adaptation, stress
signal transduction pathways, stress gene expression, senescence,
apoptosis and cardiac hypertrophy.
Our laboratory is interested in the role of oxidative stress
in aging, cancer and heart failure. Oxidants are ubiquitous. They
are byproducts of aerobic metabolism. The level of oxidants increases
as a result of radiation, intoxication of certain xenobiotics
and disease states involving inflammatory response or ischemia-reperfusion.
Experimental evidence supports the Free Radical Theory of Aging,
suggesting a role of oxidative stress in aging. Since aging is
the highest risk factor for many life-threatening diseases including
cancer and heart diseases, it is important to understand how our
body deals with oxidative stress at the cellular and molecular
level. Our research projects are moving in three directions: 1).
Molecular Mechanisms of Oxidative Stress Response. Fibroblasts
are the most abundant cell type within our body. They are scaffolds
for other cells to function on. Using human fibroblasts as an
experimental model system, we are identifying genes that are upregulated
by oxidants using genomic and proteomic approaches. These approaches
in combination with classical molecular techniques allow us to
searching for the critical molecules that control a series cellular
changes resulting from oxidant exposure such as premature senescence
and apoptosis. 2). The Relationship between Cellular Senescence
and Carcinogenesis. The risk of cancer increases exponentially
with age for humans after 40 years old. Statistics also shows
an increased mortality rate of cancer with age. To understand
the contribution of aging to cancer, we have developed a co-culture
system to study the role of cellular senescence in tumor promotion
based on the concept of the multistage carcinogenesis. We have
found that senescent cells or senescent-like cells benefit the
growth of initiated cells, indicating that these cells may function
like an endogenous tumor promoter. We are exploring the mechanism
and implication of this phenomenon. 3). The Role of Oxidative
Stress in Heart Failure. Cardiovascular disease is the number
one killer worldwide. Like cancer, the incidence of cardiovascular
diseases increases exponentially with age in the population over
45 (men) or 55 (women) years old. The heart often undergoes remodeling
as a result of aging, heart attack and many other heart diseases.
Pathological analysis reveals cardiomyocyte hypertrophy, apoptosis
of cardiomyocytes or fibrosis in failing hearts. We isolate cardiomyocytes
and fibroblasts from the heart and determine the cellular and
molecular changes produced by oxidants in these cells. We have
found that oxidants can cause hypertrophy or apoptosis of rat
cardiomyocytes in culture. Thorough analyses indicate a role of
phosphatidylinositol 3 kinase, p70 S6 kinase, MAP kinases and
transcription factor NF-AT3 in oxidant-induced cardiomyocyte hypertrophy.
Whether these molecules can serve as therapeutic targets against
cardiac hypertrophy is under investigation. On the other hand,
fibrosis is a disease involving changes in the expression of extracellular
matrix genes and many other genes by fibroblasts. We are actively
searching for the molecular control for such changes in gene expression.
Chen QM, Tu VC, Wu YW, and Bahl JJ (2000). Hyodrogen Peroxide
Dose Dependent Induction of Hypertrophy or Apoptosis of Rat Cardiomyocytes.
Arch. Biophys. Biochem., 373:242-248.
Dumont P, Burton M, Chen QM, Gonos ES, Frippiat C, Balbeur L,
Mazarati J-B, Eliaers F, Remacle J, and Toussaint O (2000). Induction
of Senescent Biomarkers by Sublethal Oxidative Stress in Normal
Human Fibroblasts. Free Radical Biol. & Med., 28: 361-373.
Chen QM, Liu J and Merrett JA (2000). Apoptosis or Senescence-Like
Growth Arrest: Influence of Cell Cycle Position, p53, p21 and
bax in H2O2 Response of Normal Human Fibroblasts. Biochem. J.,
347: 543-551.
Chen QM, Tu CY, Catania J, Burton M, Toussaint O and Dilley T
(2000) Induction of Senescent Morphology by H2O2 Involves De Novo
Protein Synthesis, Functional Rb Protein and Redistribution of
Focal Adhesion Proteins. J. Cell Sci., 113: 4087-4097.
Chen QM, Liu JP, and Tu VC (2000). Measurements of Hydrogen Peroxide
Induced Premature Senescence: Senescence-Associated b-galactosidase
and DNA Synthesis Index in Human Diploid Fibroblasts with Down-regulated
p53 or Rb. Biogerontology, 1:335-339.
Frippiat C, Chen QM, Zdanov S, Magalhaes J-P, Remacle J and Toussaint
O (2001) Subcytotoxic H2O2 stress triggers a release of TGF-b1
which induces biomarkers of cellular senescence of human diploid
fibroblasts. J Biol Chem 276: 2531-2537.
Chen QM, Prowse KR, Tu VC, Purdom S and Linskens M (2001). Uncoupling
Senescent Phenotype from Telomere Shortening in H2O2 Treated Normal
Human Fibroblasts. Exp Cell Res 265: 294-303.
Chen QM, Tu VC, Purdom S, Wood J and Dilley TD (2001). Molecular
Mechanisms of Cardiac Hypertrophy Induced by Toxicants (commissioned
review article). Cardiovasc Toxicol, 1: 267-283.
Tu VC, Bahl JJ and Chen QM. (2002) Signals of Oxidant Induced
Cardiac Myocyte Hypertrophy: Key Activation of phosphatidylinositol
3 kinase and p70S6 kinase. J Pharm Exp Therap, 300: 1101-1110.
Chen QM and Tu VC (2002) Apoptosis and Heart Failure: Mechanisms
and Therapeutic Implications. (commissioned review article) Am
J Cardiovasc Drugs 2: 43-57
Chen QM, Merrett JB, Dilley T and Purdom S (2002) Down Regulation
of p53 with HPV E6 Expression Inhibits Apoptosis but Induces Oncotic
Cell Death Associated with Mitosis in Oxidant Response of Human
Diploid Fibroblasts. Oncogene 21: 5313-5324.
Tu VC and Chen QM (2002) Distinct Roles of ERKs and p38 MAPK
in Oxidant- Induced AP-1 Activation and Cardiomyocyte Hypertrophy
(submitted).
Dilley TK, Bowden GT and Chen QM (2002) Induction of Premature
Senescence with Oxidants Confers Tumor Promoter Activity of Normal
Human Diploid Fibroblasts (submitting).
Purdom S and Chen QM (2002) p66Shc: At the Cross Road of Oxidative
Stress and Genetics of Aging (review article, submitting).
