student research day - Case Western Reserve University School of ...

Hirishikesh Gogineni
Role and Regulation of CxCR4 in Ventricular Remodeling
Hrishikesh Gogineni, Udit Agarwal, Marc Penn
Stem Cell Biology and Regenerative Medicine
The Cleveland Clinic Foundation – Lerner Research Institute
Introduction: Cardiovascular disease (CVD) is the leading cause of mortality in the United States. CVD is
mediated by ventricular remodeling which is an alteration of tissue function that results from cardiac myocyte
injury due to irreversible ischemia. Gaining a significant understanding of ventricular remodeling would be of great
use in developing potential therapies to combat CVD. As such, our project focuses on the chemokine control of
ventricular remodeling, specifically, the role and regulation of CxCR4 in ventricular remodeling post-MI. It is
currently known that CxCR4, when activated by Stromal cell Derived Factor (SDF-1), increases cardiac myocyte
survival during hypoxia. It is also known that Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF),
and Insulin-like Growth Factor (IGF-1) decrease the size of a myocardial infarct as well as the rate of cardiac
myocyte apoptosis. Our hypothesis is that cardiac myocyte derived CXCR4 participates in ventricular remodeling
post MI and is the key modulator of the effects of factors like SDF-1, PDGF, FGF, HGF and IGF-1 on ventricular
remodeling post MI.
Methods: In vitro cultures of neonatal cardiac myocytes were treated with PDGF, FGF, HGF, and IGF-1 in both
hypoxic and normoxic conditions. CxCR4 expression was analyzed qualitatively with immunostaining and
quantitatively with mRNA – RT PCR.
Left Anterior Descending (LAD) artery ligation was performed on WT C57BI/6J mice and then FGF was injected at
the infarct border. Ventricular function will be assessed using echocardiography and CxCR4 expression was
analyzed qualitatively using immunohistochemistry and quantitatively using Western blot. The results will be
compared to results which will be obtained from CxCR4 conditional KO mice.
Results: Preliminary results show that FGF increases CxCR4 expression in vitro in the neonatal cardiac myocytes.
Other growth factors did not increase CxCR4 expression to a statistically significant level. In WT control mice that
underwent LAD ligation, the peri-infarct zone shows increased CxCR4 expression as compared to areas of normal
myocardium. Results from CxCR4 conditional KO mice are not yet available for comparison.
Conclusion: Current literature shows that CxCR4 activation in cardiac myocytes, post-MI, has cardioprotective
effects by decreasing apoptosis of those myocytes. Our preliminary results suggest that FGF can also have
cardioprotective effects by increasing the expression of CxCR4. Whether CxCR4 is required for the benefits of FGF
is a question our project is still working on. If the potential of FGF is proven further in future studies, it could be a
target for therapy in patients who suffer an MI.
37