STRUCTURAL AND MOLECULAR BIOLOGY OF HEART FAILURE and DIABETES
Heart failure has a poor prognosis with approximately 40% of people dying within the first year of diagnosis. A hallmark of Heart Failure is impaired ventricular contractility. The research focus of the Kitmitto Group is the elucidation of the structural and molecular remodelling that leads to reduced contractile function in efforts to identify new therapeutic targets.
Impaired cardiac contractile performance is also a feature of patients with diabetes. Therefore a second strand to our research are studies of diabetic cardiomyopathy in models of type 1 and type 2 diabetes. Obesity is a key risk factor for the development of type 2 diabetes and so accordingly the group is investigating structural and molecular remodelling of the heart as a result of a high fat diet. Identifying changes in the early stages of disease (i.e. as a result of obesity, pre-diabetic stage) will be important for developing new strategies for preventing disease progression.
The group employs a multi-disciplinary approach combining state-of-the–art 3D electron microscopy imaging methods with complementary biochemistry, proteomics, cell and molecular biology techniques ranging from single protein studies to whole cell functional analyses.
Key research areas include:
Heart Failure and impaired Ca2+ handling – deranged dyads: Dyads are repeating regulatory microdomains formed by the juxtaposition of the transverse-tubular (t-t) network and junctional portion of the sarcoplasmic reticulum (jSR); housing the proteins that orchestrate calcium release and uptake regulating excitation-contraction (E-C) coupling.
- Whilst LV t-t remodeling is a known feature of Heart Failure our group was the first to show that the SR network also undergoes transformation disrupting dyad organization and thus communication between the E-C coupling proteins.
- Our group has also recently shown that following an myocardial infarction the t-tubules in the peri-infarct region form 'overgrown' structures; a structural platform that may promote the development of proarrhythmogenic Ca2+ waves.
- We additionally have reported how expression level changes to proteins (e.g. Junctophilin-2) underpining t-tubule orientation and dyad formation occur in heart failure and post-myocardial infarction. Studies are also focussed upon the mechanisms that regulate these proteins.
Dysfunctional cardiac energetics - a breakdown of mitochondrial networks: Ventricular remodelling and contractile dysfunction have been linked to aberrant myocardial energy substrate metabolism in heart failure patients. Excitation-contraction coupling is also dependent upon ATP generation by the mitochondria. It is the formation of membrane microdomains between the jSR and mitochondria that facilitate Ca2+ uptake from the SR stores into the mitochondria triggering pathways leading to ATP production, and thus our studies also extend to understand how changes to the nano-architecture of this microdomain impact upon cardiac contraction.
- We have shown that mitochondria are rearranged and smaller in the failing myocardium and that the relationship with the SR is disrupted.
We are therefore developing our studies to investigate how dysfunctional cardiac metabolism in heart failure and diabetes impacts upon mitochondrial function, substrate utilization, the mechanisms regulating mitochondrial fission and fusion (which influence mitochondrial morphology) and relationship with the SR.
Collaborators to interogate structure-function relationships; myocardial infarction (Cathy Holt & Nadim Malik) and diabetic cardiomyopathy (Elizabeth Cartwright)