Cardiac hypertrophy and dilatation are cardiovascular outcomes which impact negatively on the body and over time, progress to heart failure. Models of these pathological conditions, induced through various interventions, have been explored in the context of cardiovascular remodelling and stem cell activity.
In chapter 3, we demonstrated that with N(G)-nitro-l-arginine methyl ester (L NAME) administration, the level of c-Kit expression in the mouse heart significantly decreased with acute treatment (by 5 days L-NAME treatment) and these reduced levels continued to persist with chronic L-NAME treatment (6 weeks), as cardiac hypertrophy simultaneously developed by 6 weeks. It is suggested that both hyperplasia and hypertrophy of individual cardiomyocytes (hyperplasia occurring at the initial stages before hypertrophy supervenes) are likely contributing to the overall increase in both the left ventricular wall width and also a reduction in interstitial space. The reduction in c-Kit+ cells within the myocardium was thought to be a consequence of resident stem cell differentiation, mediated by hypertrophic stimulation, combined with reduced recruitment due to decreased nitric oxide (NO) production (NO is involved in stem cell recruitment via up-regulation of stromal cell-derived factor-1 (SDF-1) levels).
In chapter 4, metformin administration was shown to attenuate the reduction in cardiac stem cells that occurs in the heart during a hypertrophic stimulus (i.e. L-NAME administration). This is suggested to be likely due to an increase in adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity, resulting in increased endothelial nitric oxide synthase (eNOS) activity and inhibition of the mammalian Target of Rapamycin (mTOR) signalling. The effect of metformin administration on cardiac stem cell dynamics is likely to result in positive cardiac remodelling in the context of cardiac hypertrophy, by limiting the extent of pathological hypertrophy.
In chapter 5, the combined treatment of L-NAME and angiotensin-converting-enzyme (ACE) inhibition (captopril) demonstrated a greater decrease in c-Kit expression compared to the effects of L NAME or captopril treatment alone, suggesting that both ACE inhibition and L NAME have independent regulatory actions on c-Kit expression. The presence of ACE inhibition appeared to mediate an earlier effect on c-Kit expression levels at 2 days compared to L-NAME treatment, which has been demonstrated to occur at day 5. It is thought that the mechanism by which captopril reduced c-Kit expression was primarily via induction of ACE2/Angiotensin (Ang) 1-7 activity. Interestingly, despite the known therapeutic benefits of ACE inhibition on cardiac function in the clinical setting, high dose captopril treatment in this study demonstrated ventricular wall thinning consistent with features of heart failure.
In chapter 6, we undertook an extensive analysis of morphological changes in the heart in hypoxic or hyperoxic conditions. Intermittent hyperoxia did not result in significant wall thickening in the left ventricle, whereas intermittent hypoxia did. In the context of stem cells, c-Kit+ cells were increased with intermittent hyperoxia and decreased with intermittent hypoxia, the latter suggesting an association with the development of cardiac hypertrophy.
Overall, what is demonstrated in this thesis is that stem cells may play a role in various disease models of cardiovascular health. The stem cell response in most cases appears to be acute, occurring within days of pathological stress, and then subsiding. It is most likely, after this, that the hallmarks of cardiovascular pathology such as maladaptive remodelling take place. Despite the limitations of the experiments, a framework for further investigations has been set and understanding the mechanisms of the stem cell response would be fundamental to extending the positive influence of stem cells on cardiac remodelling beyond the acute phase.