Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila

Abstract

Background Hypoxia is often associated with cardiopulmonary diseases, which represent some of the leading causes of mortality worldwide. Long-term hypoxia exposures, whether from disease or environmental condition, can cause cardiomyopathy and lead to heart failure. Indeed, hypoxia-induced heart failure is a hallmark feature of chronic mountain sickness in maladapted populations living at high altitude. In a previously established Drosophila heart model for long-term hypoxia exposure, we found that hypoxia caused heart dysfunction. Calcineurin is known to be critical in cardiac hypertrophy under normoxia, but its role in the heart under hypoxia is poorly understood. Methods and Results In the present study, we explore the function of calcineurin, a gene candidate we found downregulated in the Drosophila heart after lifetime and multigenerational hypoxia exposure. We examined the roles of 2 homologs of Calcineurin A, CanA14F, and Pp2B in the Drosophila cardiac response to long-term hypoxia. We found that knockdown of these calcineurin catalytic subunits caused cardiac restriction under normoxia that are further aggravated under hypoxia. Conversely, cardiac overexpression of Pp2B under hypoxia was lethal, suggesting that a hypertrophic signal in the presence of insufficient oxygen supply is deleterious. Conclusions Our results suggest a key role for calcineurin in cardiac remodeling during long-term hypoxia with implications for diseases of chronic hypoxia, and it likely contributes to mechanisms underlying these disease states.

Nuclear respiratory factor 1 protects H9C2 cells against hypoxia‐induced apoptosis via the death receptor pathway and mitochondrial pathway

“…*p < .05 and **p < .01. NRF-1, nuclear respiratory factor 1; NS, not significant C Cell ell B Biology iology I International nternational and metabolism (Krejci et al, 2018;Nakada et al, 2017;Stelter et al, 2016;Sun et al, 2019;Zarndt et al, 2017). Indeed, we found that the proliferation and viability of H9C2 cells gradually decreased with increasing hypoxia treatment time.…”

“…Cardiomyocytes are sensitive to environmental conditions, especially oxygen levels. As a result, hypoxia can cause cell apoptosis and oxidative stress, thus negatively affecting cell survival, growth, and metabolism (Krejci et al, 2018; Nakada et al, 2017; Stelter et al, 2016; Sun et al, 2019; Zarndt et al, 2017). Indeed, we found that the proliferation and viability of H9C2 cells gradually decreased with increasing hypoxia treatment time.…”

Molecular characterization of serine/threonine protein phosphatase of Eimeria tenella

“…found that pp2b is also overexpressed under hypoxic conditions in Drosophila heart tissue (Zarndt et al. ). In addition, studies have shown that changes in the environment, such as heat, cold, chemical factors, and nutrition, may cause changes in protein expression (Liu et al.…”

High Heart

“…In this issue, the collaborative groups of Dr. Rolf Bodmer and Dr. Karen Ocorr investigate the cardiac specific molecular and genetic processes responsible for the three different physiological responses that Monge investigated, using the genetically amenable Drosophila system 5 . In their study, two treatments were utilized: chronic hypoxia (CH) treated flies, which were raised for 3 weeks at 4% O 2 ; or hypoxia–selected (HS) flies, which were selected for survival in 4% O 2 over more than 250 generations.…”

“…Overall, Zarndt et al 5 , have developed a powerful model for investigating the molecular effects of hypoxia on heart structure and function, and importantly demonstrated that Calcineurin signaling has a conserved role in regulating heart size. The combination of heart-specific changes in gene expression with potentially lethal phenotypes also raises the feasibility of carrying out genetic screens to investigate further the molecular events occurring during hypoxia.…”