Background

Heart failure due to diastolic dysfunction exacts a major economic, morbidity and mortality burden in the United States. Therapeutic agents to improve diastolic dysfunction are limited. It was recently found that Dynamin related protein 1 (Drp1) mediates mitochondrial fission during ischemia/reperfusion (I/R) injury, whereas inhibition of Drp1 decreases myocardial infarct size. We hypothesized that Dynasore, a small noncompetitive dynamin GTPase inhibitor, could have beneficial effects on cardiac physiology during I/R injury.

Methods and results

In Langendorff perfused mouse hearts subjected to I/R (30 minutes of global ischemia followed by 1 hour of reperfusion), pretreatment with 1 µM Dynasore prevented I/R induced elevation of left ventricular end diastolic pressure (LVEDP), indicating a significant and specific lusitropic effect. Dynasore also decreased cardiac troponin I efflux during reperfusion and reduced infarct size. In cultured adult mouse cardiomyocytes subjected to oxidative stress, Dynasore increased cardiomyocyte survival and viability identified by trypan blue exclusion assay and reduced cellular Adenosine triphosphate(ATP) depletion. Moreover, in cultured cells, Dynasore pretreatment protected mitochondrial fragmentation induced by oxidative stress.

Conclusion

Dynasore protects cardiac lusitropy and limits cell damage through a mechanism that maintains mitochondrial morphology and intracellular ATP in stressed cells. Mitochondrial protection through an agent such as Dynasore can have clinical benefit by positively influencing the energetics of diastolic dysfunction.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.

Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1α (HIF1α). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic-ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo.