Search

Abstract: Chronic hypoxia usually evokes sustained release of endogenous neurohormones, leading to β2-adrenergic receptor (β2AR) desensitization and downregulation of expression, which impacts cellular contractility. We investigated whether exogenous β2AR could compensate for the functional deficiency of β2AR in rabbit cardiomyocytes under chronic hypoxia, and whether this led to improved contractility and cellular survival. A surgical experimental model of cyanotic heart disease was established in rabbits. Adv.hβ2AR was transfected into cardiomyocytes isolated from animals subjected to 6-week systemic hypoxia. The levels of cellular contractile function, protein expression of hβ2AR, p-Akt, p-Erk, and caspase-3, and cellular survival pre- and post-Adv.hβ2AR delivery were determined. In the cyanotic cells, decreased shortening and lengthening of TPC and R50 were evident. Cellular diastolic functioning showed greater deterioration compared to the systolic function (P <0.05). In cyanotic cells, the positive inotropic response to isoproterenol was decreased (P <0.01), low levels of cellular survival were found, protein levels of β2AR, p-Akt, and p-Erk were downregulated, and protein levels of caspase-3 were upregulated. After Adv.hβ2AR delivery, enhanced contractile function was achieved (P <0.01), TPC and R50 levels recovered up to 99% and 81.7% of the normal control levels, respectively (P <0.05), and cellular survival improved (P <0.01). Our results demonstrate that overexpression of the β2AR gene in cardiomyocytes exposed to chronic hypoxia provides significant catecholamine-dependent inotropic support and cellular protection. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in the parkin gene are the most common cause of autosomal recessive Parkinson’s disease (PD). As an E3-ubiquitin ligase, Parkin is associated with mitochondrial dynamics and mitophagy. Mortalin, a molecular chaperone, is located primarily in mitochondria, where it functions to maintain mitochondrial homeostasis and antagonize oxidative stress injury. A reduced expression level of mortalin has been observed in the affected brain regions of PD patients. Mortalin also interacts with a variety of PD-related proteins and plays an indispensible role in helping native protein refolding and importing proteins into the mitochondrial matrix. Thus, the main aims of the present study were to investigate mitochondrial dysfunction induced by knockdown of mortalin and to test whether Parkin overexpression could rescue this effect. We found that lentivirus-mediated knockdown of mortalin in HeLa cells resulted in a collapse of mitochondrial membrane potential, an abnormal accumulation of reactive oxygen species and apparent alterations in mitochondrial morphology under H2O2-induced stress conditions. Remarkably, Parkin overexpression rescued these mitochondrial abnormalities. In HeLa cells expressing Parkin, co-immunoprecipitation of endogenous mortalin and wild-type Parkin was detected when they were treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In conclusion, we indicate that the relatively decreased mortalin expression level and its impaired interaction with Parkin could affect its roles in mitochondrial function. [Copyright &y& Elsevier]