Mitophagy and mitochondrial integrity in cardiac ischemia-reperfusion injury

Ischemia-reperfusion injury (IR injury), produced by initial interruption and subsequent restoration of organ blood flow, is an important clinical dilemma accompanied by various cardiac reperfusion strategies following acute myocardial infarction (AMI). Although the restored blood flow is necessary for oxygen and nutrient supply, reperfusion often results in pathological sequelae leading to elevated ischemic damage. Among various theories postulated for IR injury including vascular leakage, oxidative stress, leukocyte entrapment, inflammation and apoptosis, mitochondrial dysfunction plays an essential role in mediating pathophysiological processes with recent evidence depicting a pivotal role for impaired mitophagy in mitochondrial injury. Given the critical role for mitophagy in mitochondrial quality control and the recent reports supporting a tie between mitophagy and IR injury, this review will revisit the contemporary understanding of mitophagy in the regulation of cardiac homeostasis and update recent progresses with regards to mitophagy and cardiac IR injury. We hope to establish a role for mitophagy as a potential therapeutic target in the management of IR injury.     

Endothelial cell senescence in aging-related vascular dysfunction

Increased cardiovascular disease in aging is partly a consequence of the vascular endothelial cell (EC) senescence and associated vascular dysfunction. In this contest, EC senescence is a pathophysiological process of structural and functional changes including dysregulation of vascular tone, increased endothelium permeability, arterial stiffness, impairment of angiogenesis and vascular repair, and a reduction of EC mitochondrial biogenesis. Dysregulation of cell cycle, oxidative stress, altered calcium signaling, hyperuricemia, and vascular inflammation have been implicated in the development and progression of EC senescence and vascular disease in aging. A number of abnormal molecular pathways are associated with these underlying pathophysiological changes including Sirtuin 1, Klotho, fibroblast growth factor 21, and activation of the renin angiotensin-aldosterone system. However, the molecular mechanisms of EC senescence and associated vascular impairment in aging are not completely understood. This review provides a contemporary update on molecular mechanisms, pathophysiological events, as well functional changes in EC senescence and age-associated cardiovascular disease. This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & Megan Yingmei Zhang.     

Vascular smooth muscle cell senescence and age-related diseases: State of the art

Aging is a worldwide challenge, and it is accompanied by the accumulation of senescent cells. Cellular senescence is traditionally defined as permanent cell growth arrest and currently includes the senescence-associated secretory phenotype (SASP). There are two main types of cellular senescence, including telomere-dependent replicative senescence and stress-induced premature senescence. The process of cellular senescence is mainly controlled by two effector pathways, namely, the p53-p21 and p16-retinoblastoma protein (pRB) pathways. Vascular smooth muscle cells (VSMCs) are integral parts of arteries and play an important role in vascular structure and function. VSMC senescence may be triggered by many factors, such as angiotensin II, oxidative stress, inflammation, DNA damage, and small molecule compounds. These inducers are able to genetically and epigenetically regulate VSMC senescence. The senescence of VSMCs together with the SASP contributes to chronic vascular inflammation, the loss of arterial function, and the development of age-related diseases. Current evidence suggests that the senescence of VSMCs might be harmful to individual health, whereas its influence on the lifespan is not clear. The purpose of this paper was to review the current knowledge regarding VSMC senescence and its relevance to hypertension, atherosclerosis, and diabetes, as well as the potential mechanisms responsible for VSMC senescence in these age-related diseases.     

Long non-coding RNA cytoskeleton regulator RNA (CYTOR) modulates pathological cardiac hypertrophy through miR-155-mediated IKKi signaling

Pathological cardiac hypertrophy, which may lead to heart failure and sudden death, can be affected by multiple factors. In our previous study, we revealed that IKKi deficiency induced cardiac hypertrophy through the activation of the AKT and NF-kB signaling pathway in response to aortic banding (AB). Non-coding RNAs, mainly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a crucial role in normal developmental and pathological processes. In the present study, microarray analysis results from GEO database were analyzed, and upregulated lncRNAs in cardiac hypertrophy were identified. Of them, lncRNA cytoskeleton regulator RNA (CYTOR) obtained a fold-change of 6.16 and was positively correlated with IKBKE according to the data from The GTEx project. CYTOR knockdown significantly enhanced the inducible effect of AB operation on mice myocardial hypertrophy and Angiotensin II on cardiomyocyte hypertrophy. Moreover, miR-155 was significantly related to hypertrophic cardiomyopathy (HCM, |hsa05410) and predicted to target both CYTOR and IKBKE. Luciferase reporter and RIP assays revealed that CYTOR served as a ceRNA for miR-155 to counteract miR-155-mediated repression of IKBKE. Moreover, CYTOR knockdown reduced IKKi protein levels while activated NF-kB signaling pathway, whereas miR-155 inhibition exerted an opposing effect; the effect of CYTOR could be partially attenuated by miR-155 inhibition. Taken together, CYTOR might play a protective role in cardiac hypertrophy through miR-155 and downstream IKKi and NF-κB signaling, most possibly through serving as a ceRNA for miR-155 to counteract miR-155-mediated repression of IKBKE.     

Targeting the mTOR regulatory network in hepatocellular carcinoma: Are we making headway?

The mechanistic target of rapamycin (mTOR) pathway coordinates organismal growth and homeostasis in response to growth factors, nutrients, and cellular energy stage. The pathway regulates several major cellular processes and is implicated in various pathological conditions, including hepatocellular carcinoma (HCC). This review summarizes recent advances of the mTOR pathway, highlights the potential of the mTOR pathway as a therapeutic target, and explores clinical trials targeting the mTOR pathway in HCC. Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.