Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

Background: Ischemic heart disease remains a leading cause of death worldwide. In this study, we test the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion (IR) injury by controlling mitochondrial bioenergetics and reactive oxygen species (ROS) flux. Methods: Myocardial infarction in an acute setting of IR was examined via comparing loss vs. gain of function experiments in microRNA-210-deficient and wild type mice. Cardiac function was evaluated by echocardiography. Myocardial mitochondria bioenergetics was examined using a Seahorse XF24 Analyzer. Results: MicroRNA-210 deficiency significantly exaggerated cardiac dysfunction up to 6 weeks after myocardial IR in male, but not female, mice. Intravenous injection of microRNA-210 mimic blocked the effect and recovered the increased myocardial IR injury and cardiac dysfunction. Analysis of mitochondrial metabolism revealed that microRNA-210 inhibited mitochondrial oxygen consumption, increased glycolytic activity, and reduced mitochondrial ROS flux in the heart during IR injury. Consistently, inhibition of mitochondrial ROS with MitoQ reversed the effect of microRNA-210 deficiency. Mechanistically, we showed that mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is a novel target of microRNA-210 in the heart, and loss-of-function and gain-of-function experiments revealed that GPD2 played a key role in the microRNA-210-mediated effect on mitochondrial metabolism and ROS flux in the setting of heart IR injury. Knockdown of GPD2 negated microRNA-210 deficiency-induced increases in mitochondrial ROS production and myocardial infarction, and improved left ventricular fractional shortening and ejection fraction after the IR treatment. Conclusions: MicroRNA-210 targeting GPD2 controls mitochondrial bioenergetics and ROS flux and improves cardiac function in a murine model of myocardial infarction in the setting of IR injury. The findings suggest new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.

Significance: Calcific aortic valve disease (CAVD) is a chronic inflammatory and osteogenic condition with unknown underlying mechanism and unavailable pharmacological therapy. The present study shows that lower levels of IL-37 expression in aortic valve interstitial cells (AVICs) of diseased valves play a role in the elevated valvular osteogenic activity associated with CAVD. IL-37 inhibits NF-κB and ERK1/2 to suppress AVIC osteogenic responses, and recombinant IL-37 has a greater effect on AVICs of diseased valves. Moreover, expression of IL-37 in mice attenuates aortic valve thickening following a prolonged exposure to endotoxin or high fat diet. Thus, IL-37 is antiosteogenic in human AVICs and has the potential for limitation of CAVD progression.

Objective—: Although biglycan (BGN) and oxidized low-density lipoprotein (oxLDL) accumulation has been observed in calcific, stenotic aortic valves, their role in the pathogenesis of calcific aortic valve disease is poorly understood. We hypothesized that soluble BGN induces the osteogenic response in human aortic valve interstitial cells via Toll-like receptor (TLR) 2 and TLR4 and mediates the proosteogenic effect of oxLDL. Methods and Results—: Aortic valve interstitial cells of stenotic valves express higher levels of BGN. Stimulation of cells from normal valves with BGN increased the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) among the chondrogenic/osteogenic markers examined and caused accumulation of calcium deposits. TLR2 silencing, but not TLR4 silencing, reduced BMP-2 and ALP levels after BGN stimulation although coimmunoprecipitation revealed that BGN interacts with both TLR2 and TLR4. BGN induced the phosphorylation of extracellular signal-regulated protein kinase -1/2, p38 mitogen-activated protein kinase and nuclear factor-κB. Inhibition of extracellular-regulated kinase -1/2 markedly reduced the upregulation of BMP-2 and ALP expression by BGN whereas inhibition of p38 mitogen-activated protein kinase or nuclear factor-κB had a moderate effect. Stimulation of aortic valve interstitial cells with oxLDL upregulated BGN expression and release. Knockdown and neutralization of BGN reduced the effect of oxLDL on BMP-2 and ALP expression. Conclusion—: Extracellular soluble BGN induces the expression of BMP-2 and ALP in human aortic valve interstitial cells primarily via TLR2 and contributes to the proosteogenic effect of oxLDL. These findings highlight the potential role of soluble BGN and oxLDL in the development of calcific aortic valve disease.

MicroRNAs (miRNAs) are small noncoding RNAs functioning as crucial post-transcriptional regulators of gene expression involved in cardiovascular development and health. Recently, mitochondrial miRNAs (mitomiRs) have been shown to modulate the translational activity of the mitochondrial genome and regulating mitochondrial protein expression and function. Although mitochondria have been verified to be essential for the development and as a therapeutic target for cardiovascular diseases, we are just beginning to understand the roles of mitomiRs in the regulation of crucial biological processes, including energy metabolism, oxidative stress, inflammation, and apoptosis. In this review, we summarize recent findings regarding how mitomiRs impact on mitochondrial gene expression and mitochondrial function, which may help us better understand the contribution of mitomiRs to both the regulation of cardiovascular function under physiological conditions and the pathogenesis of cardiovascular diseases.

The extracellular matrix (ECM) is the non-cellular component in the cardiac microenvironment, and serves essential structural and regulatory roles in establishing and maintaining tissue architecture and cellular function. The patterns of molecular and biochemical ECM alterations in developing and adult hearts depend on the underlying injury type. In addition to exploring how the ECM regulates heart structure and function in heart development and repair, this review conducts an inclusive discussion of recent developments in the role, function, and epigenetic guidelines of the ECM. Moreover, it contributes to the development of new therapeutics for cardiovascular disease.