Drosophila heart as a model to study the genetic basis underlying Ischemia/Reperfusion (I/R)-induced cardiac injury: HIF1 and small HSPs. Sarah Piloto, Rolf Bodmer. Development and Aging, SBMRI, La Jolla, CA.

   Ischemic heart attack is one of the leading causes of cardiac dysfunction-related mortality in the United States. An ischemic heart attack occurs when insufficient oxygen is available for normal function leading to cardiomyocyte death. Reperfusion or the return of oxygen to the tissue after an ischemic event adds another insult, further exacerbating cardiac dysfunction. To gain a better understanding of the genetic mechanisms mediating ischemia-reperfusion-induced cardiomyopathy, we use the Drosophila heart to elucidate novel genetic mechanisms involved in the cardiac response to I/R. Genetic mechanisms involved in cardiac development and function, including sarcomeric structure and ion channel physiology, are remarkably conserved between flies and vertebrates, but interestingly, flies are relatively resistant to low oxygen levels. Using extreme hypoxic conditions (1% oxygen for 18 hours), we find that heart function is relatively well preserved when reoxygenated after this hypoxia treatment. Using this protocol, we have identified Hif1 and Hsp23 as mediators of the flys cardiac response to I/R. Hif1/Sima is a key regulator of the hypoxia response coordinating autocrine and paracrine signals to compensate for decreased oxygen levels, and Hsp23 is a small molecular weight chaperone that may participate in maintaining cardiomyocyte proteostasis in the protection against I/R-induced injury. sima null mutants do not survive our I/R regimen; however analysis of heart-specific knock-down (KD) or sima heterozygotes reveals that sima is required for maintenance of cardiac contractility and rhythmicity after I/R. Similarly, we find decreased contractility and increased arrhythmias in hearts with reduced Hsp23 levels. Taken together, Drosophila turns out to be well-suited model system to study the genetic mechanisms that underlie I/R-induced cardiac injury, and Hif1 and Hsp23 are key regulators in the cardiac response to I/R and can potentially serve as a sensitized model system to identify genetic and small molecule modifiers of a cardiac I/R response.