Protective actions of phosphoinositide 3-kinase (p110α) in a setting of cardiomyopathy

2018-06-21T04:44:29Z (GMT) by Lynette Pretorius
Heart failure affects approximately 1-3% of Western society. There is currently no cure and treatments largely delay disease progression. Consequently, there is great interest in identifying strategies that can improve cardiac function and reverse some of the negative consequences associated with heart failure. This thesis investigates the cardioprotective properties of a gene activated in the athlete’s heart [phosphoinositide 3-kinase (PI3K), p110α] in a setting of heart failure. Two double-transgenic mouse models were generated to assess the role of PI3K in a setting of cardiac stress (dilated cardiomyopathy, DCM). Mice either expressing a constitutively active mutant of PI3K (p110α) (caPI3K) or a dominant negative mutant of PI3K (p110α) (dnPI3K) were crossed with a transgenic mouse model of DCM [due to over-expression of mammalian sterile 20-like kinase 1 (Mst1)]. Increasing PI3K activity in the DCM model (caPI3K-Mst1) improved lifespan and cardiac function, whereas decreasing PI3K activity in the DCM model (dnPI3K-Mst1) had an adverse effect. The cardioprotective properties of PI3K (p110α) were mediated, at least in part, by the kinase Akt. Using the dnPI3K-Mst1 model, I was able to show that reduced PI3K (p110α) activity increases the heart’s susceptibility to atrial fibrillation (AF, the most common arrhythmia in cardiology departments worldwide). dnPI3K-Mst1 mice displayed overt atrial remodelling, varying degrees of conduction blockade and developed spontaneous AF. To assess a possible link between PI3K activity and AF in humans, PI3K (p110α) activity was measured in atrial appendages of patients with AF (acute or chronic) and compared to patients without AF. PI3K (p110α) activity was lower in patients with AF compared to patients in sinus rhythm. These results suggest that reduced PI3K (p110α) makes the heart more susceptible to the development of AF. Thus, strategies or agents that can activate PI3K (p110α) specifically in the heart may represent a useful therapeutic approach for AF. An unanticipated but novel finding was the observation that female dnPI3K-Mst1 mice showed faster disease progression than males. Prior to menopause, females are normally protected against cardiovascular disease compared with males. In contrast, in settings of aging, diabetes or hypertension [associated with depressed or defective PI3K (p110α) activity] females are more prone to cardiac disease than males. Taken together with my results, this suggests that there may be an interaction between PI3K (p110α) and estrogen, and that this interaction is essential for the cardioprotection seen in pre-menopausal women. Data obtained from dnPI3K-Mst1 mice suggests that PI3K (p110α) plays an important role in mediating cardioprotection in females. Unexpectedly, ovariectomy had a beneficial effect on the cardiac phenotype of Mst1 mice, but no significant effect in caPI3K-Mst1 or dnPI3K-Mst1 mice. The mechanisms responsible for these phenotypes will require further investigation. In summary, this thesis presents compelling evidence to support investigation into therapeutics that activate components of the PI3K (p110α) signalling pathway in a setting of cardiac stress.