Use of Rho/ROCK inhibitors to target intestinal fibrosis
Kofi
Molecular aspects of intestinal radiation-induced fibrosis.
Gervaz P, Morel P, Vozenin-Brotons MC.
Clinique de Chirurgie Digestive, Hopital Universitaire de Geneve, 24 Rue
Micheli-du-Crest, 1211 Geneve 14, Switzerland
Radiation therapy is a key component of the management of various pelvic
tumors, including prostate, gynecological, and anorectal carcinomas.
Unfortunately, normal tissues located in the vicinity of target organs
are radiosensitive, and long-term cancer survivors may develop late
treatment-related injury, most notably radiation-induced fibrosis (RIF)
of the small bowel. The cellular mediators of intestinal fibrosis are
mesenchymal cells (i.e. myofibroblasts, fibroblasts and smooth muscle
cells) which, when activated, serve as the primary collagen-producing
cells, and are responsible for excess deposition of extracellular matrix
components, eventually leading to intestinal loss of function. For
decades, the underlying mechanisms involved in chronic activation of
myofibroblasts within the normal tissues were unknown, and the fibrotic
process, which ensued, was considered irreversible. Recent advances in
the pathogenesis of RIF have demonstrated prolonged upregulation of
fibrogenic cytokines, such as Transforming growth factor-beta1
(TGF-beta1) and its main downstream effector, Connective tissue growth
factor (CTGF), in the myofibroblasts of irradiated small bowel.
TGF-beta1-mediated activation of CTGF gene expression is controlled by
Smads, but recently Rho/ROCK signaling has emerged as an alternative
pathway involved in the control of CTGF expression in intestinal
fibrosis. This article underlines the clinical relevance of RIF as it
relates to damage to the small bowel, provides insight to its molecular
biology, and finally unveils the potential role of Rho-ROCK inhibitors
as emerging strategies to promote RIF reversal.
Publication Types:
* Research Support, Non-U.S. Gov't
* Review
PMID: 19355909
Jim Godamnski
My research indicates that all muscle cells produce collagen in amounts that
are significant.
"Kofi" <ko...@anon.un> wrote in message
news:kofi-A7F6DC.0...@news.east.earthlink.net...
Ernie
> Kofi,
>
> My research indicates that all muscle cells produce collagen in amounts that
> are significant.
>
>
> - Show quoted text -
The biggest muscle asshole farrel has is between her ears. Ernie
Kofi
Trends Cardiovasc Med. 2007 Aug;17(6):206-11.
Leptin as a cardiac hypertrophic factor: a potential target for
therapeutics.
Karmazyn M, Purdham DM, Rajapurohitam V, Zeidan A.
Department of Physiology and Pharmacology, Schulich School of Medicine
and Dentistry, University of Western Ontario, London, Ontario, Canada
N6A 5C1.
The satiety factor leptin has received extensive attention especially in
terms of its potential role in appetite suppression and regulation of
energy expenditure. Once considered to be solely derived from adipose
tissue, which accounts for the greatly increased levels observed in
obese subjects, it is now apparent that leptin can be produced by a
multiplicity of tissues, including the heart, where it appears to
function in an autocrine and paracrine manner. Plasma leptin
concentrations are also elevated in patients with heart disease
including those with congestive heart failure. Leptin exerts its
biological effects via a family of receptors termed Ob-R. In cardiac
cells, one of leptin's primary actions is to produce cardiomyocyte
hypertrophy through multifaceted cell signaling mechanisms including
stimulation of mitogen-activated protein kinase and activation of the
RhoA/Rho kinase (ROCK) pathway. The hypertrophic effect of leptin
suggests that it may contribute to myocardial remodeling after cardiac
injury and offers the potential targeting of the leptin system as a
novel cardiac therapy.
Publication Types:
* Research Support, Non-U.S. Gov't
* Review
PMID: 17662916
experiments suggest that leptin-deficient animals develop left
ventricular (LV) hypertrophy, but data relating circulating leptin
levels to cardiac structure and function in subjects >70 years is
contradictory; leptin concentrations were inversely associated with LV
mass, LV wall thickness, and left atrial size (p <0.04 for all); the top
gender-specific tertile of leptin was associated with an adjusted LV
mass 16 g lower compared with the lowest tertile; leptin levels were not
associated with LV fractional shortening, transmitral early/late
diastolic filling velocities, or LV end-diastolic diameter (p >0.16);
cross-sectional observations suggest a cardioprotective influence of
leptin on LV remodeling consistent with experimental data and may
provide insight into the potential role of leptin resistance as a
mediator of obesity-associated cardiomyopathy [PMID 19660619]
cardiac myocytes depend on a delicate balance of glucose and free fatty
acids as energy sources, a balance that is disrupted in pathological
states such as diabetic cardiomyopathy and myocardial ischaemia; there
are two families of cellular glucose transporters: the
facilitated-diffusion glucose transporters (GLUT); and the
sodium-dependent glucose transporters (SGLT); it was once thought only
GLUT isoforms, GLUT1 and GLUT4, are responsible for cardiac myocyte
glucose uptake but SGLT1 is also an important glucose transporter in
heart; SGLT1 is largely localized to the cardiac myocyte sarcolemma;
SGLT1 expression changes in disease states in both humans and mouse
models; SGLT1 expression is upregulated two- to three-fold in type 2
diabetes mellitus and myocardial ischaemia; in humans with severe heart
failure, functional improvement following implantation of left
ventricular assist devices leads to a two-fold increase in SGLT1 mRNA;
acute administration of leptin to wildtype mice increases cardiac SGLT1
expression approximately seven-fold; insulin- and leptin-stimulated
cardiac glucose uptake is significantly inhibited by phlorizin, a
specific SGLT1 inhibitor [PMID 19509029]
in diabetes leptin may interact with endothelin 1 (ET-1) in fibronectin
(FN) synthesis and cardiomyocyte hypertrophy (two characteristic
features of diabetic cardiomyopathy); in cultured human umbilical vein
endothelial cells (HUVECs) and neonatal rat cardiomyocytes, glucose
caused increased FN mRNA and protein expression in HUVECs and
cardiomyocytes hypertrophy along with upregulation of ET-1 mRNA, leptin
mRNA and protein; glucose-mimetic effects were seen with leptin and
ET-1; a leptin receptor antagonist and dual endothelin A endothelin B
(ETA/ETB) receptor blocker normalized such abnormalities; hearts from
the diabetic animals showed hypertrophy and similar mRNA changes [PMID
19391127]
protection against myocardial ischemia-reperfusion injury, including
that induced by leptin, involves activation of the reperfusion injury
salvage kinase pathway and inhibition of the mitochondrial permeability
transition pore; leptin-induced cardioprotection, however, is blunted in
obesity because of downregulation of the leptin receptor (OB-R); in
hearts from Wistar and Zucker lean rats that express functional OB-R and
Zucker obese (fa/fa) rats with a nonfunctional OB-R; in Langendorff
experiments, leptin (10 nM) caused significant reductions in infarct
size in hearts from Wistar (leptin treated, 32.4% vs. control, 53.2%)
and Zucker lean animals (leptin treated, 25.2% vs. control, 53.9%) but
hearts from (fa/fa) did not exhibit significant decreases in infarct
size; leptin increased p44 and p42 phosphorylation in Wistar rat hearts
by 103.9% and 157.3%, respectively, and by 97.0% and 158.1% in hearts
from Zucker lean rats; Akt/serine-473 phosphorylation was increased in
Wistar hearts by 96.7%, whereas Akt/threonine-308 phosphorylation was
elevated by 43.9% in Zucker lean rat hearts; leptin did not influence
Akt or p44/42 phosphorylation in (fa/fa) animals; leptin treatment
delayed mitochondrial permeability transition pore opening by 43% and
30.9%, respectively, in cardiomyocytes from Wistar and Zucker lean rat
hearts but not in cardiomyocytes from (fa/fa) [PMID 19390347]