Diabetic Modulation of Caveolar Proteins, Infarct Tolerance and Ischaemic Preconditioning

Abstract

Ischaemic heart disease (IHD) remains a leading cause of death worldwide and clinical therapies to improve cardiac outcomes following associated acute myocardial infarction (AMI) remain elusive. Subjecting the heart to transient pharmacological or ischaemic conditioning stimuli prior to or immediately following prolonged ischaemia potently protects hearts from ischaemia-reperfusion (I-R) injury in experimental models; however, this is generally ineffective in the clinical setting, where among other factors, patients suffer one or more co-morbidities. Indeed, multi-morbidity is now dominant in those with IHD. Increasingly common diabetes is a major risk factor for AMI, and not only doubles the risk of AMI but may also worsen cardiac injury and impair or negate normally protective conditioning stimuli. However, effects of diabetes on ischaemic tolerance and cardioprotection are highly variable in both humans and animal models, complicating strategic development of protective therapies. Diabetic disease duration and progression may play critical roles in governing myocardial I-R tolerance, and cardiac outcomes may differ in type 1 diabetes (T1D) vs. more widespread type 2 diabetes (T2D). Changes in I-R tolerance and cardioprotection with diabetes likely involves multiple mechanisms, including disruption of membrane structure and function and depletion of membranous caveolins. These proteins, together with cavins, play critical structural and functional roles in membrane signalling domains, known as caveolae, and appear essential for cardioprotective conditioning and other responses. Emerging evidence indicates caveolin proteins may be sensitive to hyperglycaemia and hyperlipidaemia; however, studies are limited to acute in vitro and T1D models, with effects in relevant chronic models of diabetes warranting further study. While little is known about the regulation of caveolins, they may be depleted with saturated fat vs. increased with the omega-3 fatty acid, α-linolenic acid (ALA). Studies also indicate differential modulation via pharmacological interventions and hyperglycaemic conditions, indicating restoration of caveolins under diabetic conditions may be possible. However, whether such changes are capable of improving outcomes following infarction is unknown. Studies undertaken in the course of this doctoral project therefore aimed to characterise caveolar protein expression, I-R tolerance and cardioprotection in in vitro and in vivo models of T1D and T2D, and to test whether ALA supplementation might improve cardiac outcomes.