Patients with J wave syndromes (JWS), such as Brugada syndrome and early repolarization syndrome are vulnerable to life-threatening ventricular arrhythmias. Factors that promote JWS are not fully understood and models of the disease are limited. In this episode, Mu Chen and Peng-Sheng Chen describe their work, which shows that activation small-conductance calcium-activated potassium (SK) current (IKAS) in conjunction with inhibition of the sodium current with CyPPA induces JWS-associated phenotypes in perfused rabbit hearts. Moreover, inhibition of IKAS in this model eliminated JWS-like manifestations. The results of this study provide important insight into the drivers of JWS and suggest that IKAS inhibition be further explored for JWS.
Prostate cancer is a highly heterogenous disease, both within the primary tumor of a single individual and among individuals with the disease; therefore, diagnosis and determination of appropriate treatment options are challenging. In this episode, Simpa Salami, Ganesh Palapattu, and colleagues investigated the ability of commercially available gene expression assays to detect the coexistence of high-grade unsampled disease in formalin-fixed paraffin-embedded primary prostate tumor samples. The results of this study indicate that low- and high-grade foci have distinct prognostic gene expression profiles and suggest that sequencing of a low-grade area of a given tumor may not provide information about unsampled areas. Moreover, this work indicates that results from expression-based assays may not present the full picture of an individual’s disease.
Maternal diet has profound, long-lasting effects on offspring. For example, maternal malnutrition results in fetal exposure to excessive glucocorticoid, which can result in metabolic reprogramming and hypertension. In this episode, Toshiro Fujita and colleagues exposed pregnant rodents to a low-protein diet or to the synthetic glucocorticoid dexamethasone and demonstrated that the offspring of these dams were prone to salt-sensitive hypertension. In utero glucocorticoid exposure resulted in aberrant DNA methylation of hypothalamic angiotensin receptor type 1a, resulting in increased expression. Moreover, mice lacking the DNA methyltransferase 3a became hypertensive in the absence of glucocorticoid exposure, while animals lacking the angiotensin receptor were protected from prenatal glucocorticoid exposure-induced hypertension. Together, these results reveal epigenetic modulation of angiotensin signaling underlies development of hypertension that results from prenatal exposure to glucocorticoids.
Type 1 diabetes (T1D) is an autoimmune disease characterized by an inability to produce insulin as the result of insulin-secreting pancreatic β cell loss. Neutrophils are key mediators of several autoimmune disorders; however, the contribution of these cells to T1D etiology is poorly defined. In this episode, Manuela Battaglia and colleagues discuss their work, which identifies an abnormal neutrophil signature that is present in the blood and pancreas of individuals with T1D and those that are at risk of disease. Cumulatively, these results suggest that neutrophils should be explored as a therapeutic target for T1D.
Maternal obesity has been associated with adverse outcomes in offspring; however, it is not clear how maternal obesity or high-fat diet (HFD) impart long-term effects on offspring. In this episode, Julie Mirpuri and colleagues use murine models to evaluate the effects of HFD during pregnancy on offspring. The offspring of HFD-fed mothers developed a microbiome that was distinctly different than that of offspring of mothers on a regular diet. Moreover, IL-17–producing type 3 innate lymphoid cells (ILC3s) were increased the offspring of HFD-fed mothers, a phenotype linked to the HFD-associated microbiota. The offspring of HFD-fed mothers were also more susceptible to necrotizing enterocolitis. Together, these results indicate that maternal HFD influences the offspring microbiome, thereby increasing ILC3s and susceptibility to inflammatory insult.