Matrix metalloproteinase2 (MMP2) was recently revealed to have targets and
actions within the cardiac myocyte. In ischemia/reperfusion (I/R) injury, MMP2 is
activated and degrades troponin I (TnI) and actinin. The regulation of intracellular
MMP2 activity is relatively unknown and is thus the subject of this thesis.
The localization of MMP2 in caveolae of endothelial cells suggests that
caveolin1 (Cav1) may play a role in regulating MMP2. Whether Cav1 is responsible
for regulating MMP2 in the heart is unknown.
A Cav1 knockout mouse model was used to explore the role Cav1 may play in
the regulation of MMP2 activity. The initial studies found that MMP2 and Cav1 were
colocalized in cardiomyocytes and that MMP2 activity in Cav1/ hearts was markedly
enhanced. Additionally, the caveolin scaffolding domain inhibited MMP2 activity in a
concentrationdependent manner.
To explore whether increased MMP2 in Cav1/ hearts translates to impaired
cardiac function, Cav1+/+ and Cav1/ isolated working hearts were physiologically
challenged with increasing increments of left atrial preload followed by increasing
concentrations of isoproterenol. Cav1/ hearts show similar or better cardiac function
compared to Cav1+/+ hearts following preload challenge or adrenergic stimulation in
vitro, and this appears unrelated to changes in MMP2.
Though the function of Cav1/ hearts appears similar to that of Cav1+/+ hearts
during physiological situations, whether this is the case during I/R injury is not known.
Cav1+/+ and Cav1/ isolated working mouse hearts exposed to global, noflow ischemia
showed no functional differences. However, Cav1/ hearts had significantly higher
levels of both TnI and actinin following I/R than Cav1+/+ hearts.
Posttranslational modifications of the intracellular MMP2 substrates could alter
susceptibility to MMP2 proteolysis. Isolated working mouse hearts were exposed to
isoproterenol and/or I/R injury to examine the phosphorylation status of TnI.
Isoproterenol and I/R both result in the phosphorylation of TnI, however, isoproterenol
lead to a more highly phosphorylated form of TnI than that observed in hearts exposed
I/R alone.
These and subsequent studies will further reveal the molecular mechanisms that
underlie the complex interactions between Cav1 and MMP2. This may eventually lead
to a novel avenue of therapeutic intervention for heart diseases.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1383 |
| Date | 11 1900 |
| Creators | Chow, Ava Kalyca |
| Contributors | Schulz, Richard (Paediatrics and Pharmacology), Daniel, Edwin E. (Pharmacology), Baksh, Shairaz (Paediatrics), Kassiri, Zamaneh (Physiology), Bernatchez, Pascal (Anesthesiology, Pharmacology and Therapeutics) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 10546714 bytes, application/pdf |
| Relation | Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol 2007; 152:189205., Kandasamy AD, Chow AK, Ali MA, Schulz R. Matrix metalloproteinase2 and myocardial oxidative stress injury: beyond the matrix. Cardiovasc Res 2010; 83: 413 423., Chow AK, Cena J, ElYazbi AF, Crawford BD, Holt A, Cho WJ, Daniel EE, Schulz R. Caveolin1 inhibits matrix metalloproteinase2 activity in the heart. J Mol Cell Cardiol 2007; 42:896901., Cho WJ, Chow AK, Schulz R, Daniel EE. Matrix metalloproteinase2, caveolins, focal adhesion kinase and cKit in cells of the mouse myocardium. J Cell Mol Med 2007; 11:10691086., Chow AK, Daniel EE, Schulz R. Cardiac function is not significantly diminished in hearts isolated from young caveolin1 knockout mice. Am J Physiol Heart Circ Physiol. In press. |
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