Cardioprotective effect of Notch signaling on the development of myocardial infarction complicated by diabetes mellitus

Abstract

The present study aimed to elucidate the role of Notch signaling in the development of myocardial infarction (MI) concomitant with diabetes in vivo and in vitro and evaluated the therapeutic effect of the Notch signaling in vitro. Streptozotocin-induced diabetic rats were subjected to 25 min of ischemia and 2 h of reperfusion. Cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) isoenzyme levels were detected. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride staining. Myocardial apoptosis and fibrosis were examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Masson Trichrome staining, respectively. The mRNA and protein levels of Notch signaling components, including Notch1, Notch4, Delta-like 1, Jagged1, Mastermind-like protein 1 and p300, were quantified by reverse transcription-quantitative polymerase chain reaction and western blotting analyses, respectively. H9c2 cells were treated with/without 33 mM high glucose (HG) and/or subjected to hypoxia in the presence/absence of Jagged1. Cell viability and apoptosis were determined by MTT assay and Annexin V-fluorescein isothiocyanate/propidium iodide assay. Levels of the Notch signaling pathway members were examined. The present findings revealed that diabetes elevated CK-MB and cTnT, increased infarct size, induced myocardial apoptosis and inhibited the Notch signaling pathway in vivo after ischemia/reperfusion. Ischemia/reperfusion augmented the severity of MI in diabetic rats. Furthermore, HG reduced cell viability and induced cell apoptosis in H9c2 cells after hypoxia exposure, which was inhibited by Jagged1. We also found that HG inhibited Notch signaling in H9c2 cells after hypoxia, whereas Jagged1 exerted its cardioprotective effect on hypoxic injury (in HG environments or not) by activating the Notch signaling pathway. In conclusion, these findings suggest that diabetes promoted the progression of MI in vivo and in vitro via the inhibition of the Notch signaling pathway. Jagged1 may protect against MI in in vitro models by activating Notch signaling.

Cardioprotective effects of the total flavonoids of <i>Polygonum cuspidatum</i> Sieb. et Zucc. Root extract on experimental myocardial infarction in mice

“…Myocardial necrosis caused by local ischemia and hypoxia is one of the main causes of MI-induced heart failure. Reducing MIS and improving myocardial function have become the main therapeutic targets of drugs against MI [21]. In the present study, FHZ treatment decreased the serum cTnT level and MIS value in the MI mice, indicating that FHZ had therapeutic effects on MI.…”

Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

“…This is in concordance with a negative effect of Dll4dependent Notch1 signaling on angiogenesis (47,52,53). It is, however, likely that different ligands are important in different diabetes contexts, as Jagged1 seems to be central for nephropathy (49) and is induced in the retina (42) and myocardium (54). This is another example of the high versatility of Notch signaling that has many well-documented tissue-and cell-type-specific outputs (10, 11).…”

Sitagliptin protects diabetic rats with acute myocardial infarction through induction of angiogenesis: role of IGF-1 and VEGF

“…Diabetes mellitus was reported to promote the progression of MI by inhibiting the Notch signaling pathway that regulates cell proliferation, death, differentiation, cell-to-cell communication and angiogenesis. Activating the Notch pathway has been reported to alleviate I/R and hypoxic injuries (Wu, Yu, Zhang, & Zhang, 2017). Although angiogenesis plays a role in the pathogenesis of diabetic microvascular complications in some tissues like the retina, DM impairs the formation of small blood vessels in other tissues like the heart and skin (Cheng & Ma, 2015).…”