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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #212352
Title: Identification of a novel cardioprotective program sustaining right ventricular output in response to chronic oxygen deprivation

Author
item ZUNGU, MAKHOSAZANE - UNIV CAPE TOWN
item Young, Martin
item ESSOP, FAADIEL - UNIV CAPE TOWN

Submitted to: Circulation
Publication Type: Abstract Only
Publication Acceptance Date: 7/20/2006
Publication Date: 10/31/2006
Citation: Zungu, M., Young, M.E., Essop, M. 2006. Identification of a novel cardioprotective program sustaining right ventricular output in response to chronic oxygen deprivation [abstract]. Circulation. 114(18):209-210.

Interpretive Summary:

Technical Abstract: Chronic exposure to hypoxia results in pulmonary hypertension, increasing load on the right ventricle (RV) and ultimately leading to the onset of RV hypertrophy. An emerging paradigm suggests that exposure to chronic hypoxia triggers adaptive regulatory pathways allowing the RV to meet higher energetic demands in response to increased load. However, molecular mechanisms underlying such cardioprotection are unclear. Here, we hypothesized that chronic hypoxia results in augmented mitochondrial bioenergetic capacity in the RV, thereby sustaining its contractile function. Wistar rats were exposed to 2 weeks hypobaric hypoxia (11% O2) and compared to normoxic controls. With hypoxia, RV/left ventricle (LV) weight ratio and RV developed pressure were increased by 69.6 +/- 5.4% and 56 +/- 5.7%, respectively, vs. normoxic controls (n>=4, p<0.05). However, LV/body weight ratio and LV developed pressure were not significantly altered with hypobaric hypoxia. Right and left ventricular mitochondria were separately isolated to assess energetic status. Following hypobaric hypoxia, RV polarographic O2 consumption and ADP/O were increased by 32.9 +/- 2.2% and 33 +/- 1.5%, respectively, vs. normoxic controls (n>=4, p<0.05). Moreover, proton leak (measured by oligomycin insensitive respiration) was reduced (n>=4, p<0.05). In parallel, several genes regulating mitochondrial respiratory function, i.e., cytochrome oxidase II, cytochrome oxidase IV, and uncoupling protein 2 (UCP2), were upregulated (n>=10, p<0.05), while UCP3 was downregulated (p<0.05) in the RV. Also, nuclear respiratory factor 1 (transcriptional modulator of mitochondrial respiration genes) was increased (59.7 +/- 4.9%) in the RV vs. normoxic controls (n=14, p<0.001). However, this gene program was not induced in the LV, and no significant changes in LV mitochondrial respiratory function were found in response to hypobaric hypoxia. Our data therefore suggest distinct metabolic remodeling in the right and left ventricles in response to chronic hypobaric hypoxia. Moreover, we have identified for the first time a cardioprotective program in the RV that links the efficiency of mitochondrial oxidative phosphorylation and respiratory function to sustained RV contractile function in response to the increased load.