Background
Heart failure is a major cause of mortality in obesity and can occur in the absence of other established risk factors such as hypertension. This is known as obese cardiomyopathy and an alteration in cardiac metabolism is thought to be one of the key drivers of the disease, however, little is known on the contributing factors. Serum levels of the Alzheimer’s disease protein amyloid beta 42 (Aβ42) increase in obesity and our research group has recently found that mice administered Aβ42, to increase levels to those seen in obesity, develop cardiac dysfunction.
Purpose/Aims
The aim of our research is to determine the mechanisms of action of Aβ42 on cardiomyocytes in order to better understand the pathogenesis of the disease and potentially uncover therapeutical targets to prevent and treat it.
Methods
Hearts from mice administered Aβ42 or scrambled peptide were examined using RNA sequencing, western blotting and qPCR. H9C2 cardiomyocytes were used to screen for receptors and signalling pathways mediating the effects of Aβ42.
Results/Conclusion
Analysis of RNA sequencing data revealed a number of signalling pathways that may be important in Aβ42 mediated changes including the nerve growth factor and fibroblast growth factor signalling pathways. Furthermore, mice administered Aβ42 and Aβ42 treated cardiomyocytes showed evidence of inflammatory and ER stress responses. Inhibition of protein kinase D (PKD) in Aβ42 treated cardiomyocytes impaired these responses, suggesting it may be an important signalling molecule.
To further understand these findings, the importance of PKD in Aβ42-mediated cardiomyopathy will be examined in mice with a cardiac specific loss of PKD activity. In addition, the effectiveness of drugs developed for the treatment of Alzheimer’s disease to preventing obese cardiomyopathy in a mouse model of obesity will be examined.