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Additional file 1. Supplementary Figures and Tables.

Background Spaceflight or microgravity conditions cause myocardial atrophy and dysfunction, contributing to post-flight orthostatic intolerance. However, the underlying mechanisms remain incompletely understood and preventive approaches are limited. This study investigated whether and how losartan, a blocker of angiotensin-II receptor, preserved cardiomyocyte size and prevented myocardial dysfunction during microgravity. Method Adult male mice were suspended with their tails to simulate microgravity. Echocardiography was performed to assess myocardial function. Heart weight and cardiomyocyte size were measured. NADPH oxidase activation was determined by analyzing membrane translocation of its cytosolic subunits including p47 phox , p67 phox and Rac1. Heart tissues were also assayed for oxidative stress, p47 phox phosphorylation (Ser345), MuRF1 protein levels and angiotensin-II production. Results Tail-suspension for 28 days increased angiotensin-II production in hearts, decreased cardiomyocyte size and heart weight, and induced myocardial dysfunction. Administration of losartan preserved cardiomyocyte size and heart weight, and prevented myocardial dysfunction in tail-suspended mice. These cardioprotective effects of losartan were associated with inhibition of p47 phox phosphorylation (Ser345), NADPH oxidase and oxidative stress in tail-suspended mouse hearts. Additionally, the NADPH oxidase inhibitor, apocynin, also reduced oxidative stress, preserved cardiomyocyte size and heart weight, and improved myocardial function in tail-suspended mice. Furthermore, losartan but not apocynin attenuated tail-suspension-induced up-regulation of MuRF1 protein in mouse hearts. Conclusions Administration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction under microgravity by blocking p47 phox phosphorylation and NADPH oxidase activation, and by inhibiting MuRF1 expression. Thus, losartan may be a useful drug to prevent microgravity-induced myocardial abnormalities.

The authors regret that they mixed up the immunoblot images in the above article, and mistakenly placed the wrong images for Fig. 1 C1 and C2. Please find the corrected Fig. 1 C1 and C2 below. (Figure Presented).

Doxorubicin is an established anticancer medication infamous for its bright colouration and extremely toxic side effects. Emerging studies support that the imbalance between acetylation and deacetylation disrupts the autophagic flux leading to doxorubicin-induced cardiotoxicity. Vacuolar ATPases are a family of electrogenic proton pumps present on the lysosomal membrane that create an acidic environment for proteases to degrade proteins. Our preliminary study found that acetylated Vacuolar ATPase subunit V0 D1 levels increased in doxorubicin-injected mouse hearts. However, it is unknown how acetylation of subunit V0 D1 is modulated and whether this modification plays a role in doxorubicin-induced cardiotoxicity. The focus of the project is to identify the specific acetylase involved in acetylating Vacuolar ATPase subunit V0 D1 using histone acetyltransferase (HAT) inhibitors and its potential role in doxorubicin-induced cardiotoxicity. For example, Garcinol is a p300 HAT inhibitor derived from a plant called Garcinia Indica and past studies revealed that Garcinol natural properties have cardioprotective effects. Cardiomyocytes will be used as a model and cell viability, apoptosis, lactate dehydrogenase release, autophagic flux, Vacuolar ATPase activity (lysosomal pH), and Vacuolar ATPase subunit V0 D1 acetylation will be analyzed. It is hypothesized that selective HAT inhibition will prevent Vacuolar ATPase subunit V0 D1 hyperacetylation and allow for regulated autophagic flux to restore cell viability during doxorubicin-induced cardiotoxicity.

Calpain plays a critical role in cardiomyopathic changes in type 1 diabetes (T1D). This study investigated how calpain regulates mitochondrial reactive oxygen species (ROS) generation in the development of diabetic cardiomyopathy. T1D was induced in transgenic mice overexpressing calpastatin, in mice with cardiomyocyte-specific capn4 deletion, or in their wild-type littermates by injection of streptozotocin. Calpain-1 protein and activity in mitochondria were elevated in diabetic mouse hearts. The increased mitochondrial calpain-1 was associated with an increase in mitochondrial ROS generation and oxidative damage and a reduction in ATP synthase-α (ATP5A1) protein and ATP synthase activity. Genetic inhibition of calpain or upregulation of ATP5A1 increased ATP5A1 and ATP synthase activity, prevented mitochondrial ROS generation and oxidative damage, and reduced cardiomyopathic changes in diabetic mice. High glucose concentration induced ATP synthase disruption, mitochondrial superoxide generation, and cell death in cardiomyocytes, all of which were prevented by overexpression of mitochondria-targeted calpastatin or ATP5A1. Moreover, upregulation of calpain-1 specifically in mitochondria induced the cleavage of ATP5A1, superoxide generation, and apoptosis in cardiomyocytes. In summary, calpain-1 accumulation in mitochondria disrupts ATP synthase and induces ROS generation, which promotes diabetic cardiomyopathy. These findings suggest a novel mechanism for and may have significant implications in diabetic cardiac complications.