Since impaired mitochondrial ATP production in cardiomyocytes is thought to lead to heart failure, a drug that protects mitochondria and improves ATP production under disease conditions would be an ...attractive treatment option. In this study, we identified small-molecule drugs, including the anti-parasitic agent, ivermectin, that maintain mitochondrial ATP levels under hypoxia in cardiomyocytes. Mechanistically, transcriptomic analysis and gene silencing experiments revealed that ivermectin increased mitochondrial ATP production by inducing Cox6a2, a subunit of the mitochondrial respiratory chain. Furthermore, ivermectin inhibited the hypertrophic response of human induced pluripotent stem cell-derived cardiomyocytes. Pharmacological inhibition of importin β, one of the targets of ivermectin, exhibited protection against mitochondrial ATP decline and cardiomyocyte hypertrophy. These findings indicate that maintaining mitochondrial ATP under hypoxia may prevent hypertrophy and improve cardiac function, providing therapeutic options for mitochondrial dysfunction.
•High-throughput image-based phenotypic screens based on mitochondrial ATP under hypoxia were developed.•Mitochondrial ATP protectors, including ivermectin, were identified in cardiomyocytes under hypoxia.•Ivermectin increased mitochondrial ATP production by inducing Cox6a2.•Mitochondrial ATP protectors inhibited hypertrophic responses in human iPSC-derived cardiomyocytes.
Impaired mitochondrial ATP production in cardiomyocytes is one of the major causes of heart failure. A drug that maintains ATP production would, therefore, be an attractive heart failure treatment option. We performed high-throughput image-based screens under hypoxia, and identified mitochondrial ATP protectors, including the anti-parasite drug, ivermectin. We show that ivermectin increased mitochondrial ATP production by inducing Cox6a2 expression and inhibited the hypertrophic response of human iPSC-derived cardiomyocytes. Pharmacological inhibition of importin β, a target of ivermectin, exhibited similar protective effects. Our studies indicate that compounds maintaining mitochondrial ATP under hypoxia may prevent pathological hypertrophy and improve cardiac function.
Fasiglifam (TAK‐875) is a free fatty acid receptor 1 (FFAR1)/G‐protein–coupled receptor 40 (GPR40) agonist that improves glycemic control in type 2 diabetes with minimum risk of hypoglycemia. ...Fasiglifam potentiates glucose‐stimulated insulin secretion (GSIS) from pancreatic β‐cells glucose dependently, although the precise mechanism underlying the glucose dependency still remains unknown. Here, we investigated key cross‐talk between the GSIS pathway and FFAR1 signaling, and Ca2+ dynamics using mouse insulinoma MIN6 cells. We demonstrated that the glucose‐dependent insulinotropic effect of fasiglifam required membrane depolarization and that fasiglifam induced a glucose‐dependent increase in intracellular Ca2+ level and amplification of Ca2+ oscillations. This differed from the sulfonylurea glimepiride that induced changes in Ca2+ dynamics glucose independently. Stimulation with cell‐permeable analogs of IP3 or diacylglycerol (DAG), downstream second messengers of Gαq‐FFAR1, augmented GSIS similar to fasiglifam, indicating their individual roles in the potentiation of GSIS pathway. Intriguingly, the IP3 analog triggered similar Ca2+ dynamics to fasiglifam, whereas the DAG analog had no effect. Despite the lack of an effect on Ca2+ dynamics, the DAG analog elicited synergistic effects on insulin secretion with Ca2+ influx evoked by an L‐type voltage‐dependent calcium channel opener that mimics glucose‐dependent Ca2+ dynamics. These results indicate that the Gαq signaling activated by fasiglifam enhances GSIS pathway via dual potentiating mechanisms in which IP3 amplifies glucose‐induced Ca2+ oscillations and DAG/protein kinase C (PKC) augments downstream secretory mechanisms independent of Ca2+ oscillations.
We determined the clinical characteristics of adult-onset NIDDM patients positive for antiglutamic acid decarboxylase antibody (GAD-Ab). The subjects were 40 patients who were diagnosed after the age ...of 20 years without ketosis at the onset, who required insulin therapy and were positive for GAD for 7 years of follow-up. The mean age at the time of the study was 53 years and the duration of diabetes was 7 years. The mean body mass index (BMI) was 20. 7. The controls were 18 adult-onset GAD-Ab-negative NIDDM patients who were matched for gender, age at the time of the study, disease duration and BMI. The mean duration from the onsetof diabetes to insulin therapy was 1. 6 years in the GAD-Ab-positive group and 3. 3 years in the negative group. The incidence a history of obesity was 22.5% inthe positive group and 16% in the negative group, and the incidence of a BMI over 22 was 30% in the positive group and 38% in the negative group. The GAD-positive group showed greater ICA and/or ICA 512 prevalence than the negative group. DR 4 and/or DR 9 were not significantly different in the two groups, while A 24 in the GAD-Ab positive group was 36%(0% in the GAD-Ab-negative group). Adult-onset GAD positive diabetes may cause autoimmune-pancreatic β-cell destruction.
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