Abstract
Ample clinical case reports suggest a high incidence of cardiomyopathy in diabetes mellitus (DM). Recent evidence supports an essential role of trehalose (TLS) in cardiomyocyte survival signaling. Our previous study found that prokineticin2 (PK2) was involved in the process of diabetic cardiomyopathy (DCM). The present study examined the protective effects and mechanisms of TLS on DM-induced cardiomyocyte injury in mice and H9c2 cardiomyocytes. C57BL/6J mice were intraperitoneally injected with 50 mg·kg−1·d−1 streptozotocin for five consecutive days to establish an experimental diabetic model and then administered TLS (1 mg·g−1·d−1, i.p.) for two days every 4 weeks and given 2% TLS in drinking water for 24 weeks. Echocardiography, myocardial structure, apoptosis, pyroptosis, autophagy, and the PK2/PKR pathway were assessed. Cardiomyocytes exposed to high glucose (HG) were treated with TLS in the absence or presence of the PK2 antagonist PKRA7, and proteins involved in apoptosis, autophagy, and pyroptosis and the PK2/PKR pathways were evaluated using Western blot analysis. Diabetic mice demonstrated metabolic disorder, abnormal myocardial zymograms, and aberrant myocardial systolic and diastolic function, which were accompanied by pronounced apoptosis, pyroptosis, and dampened autophagy. TLS treatment relieved these effects. PK2 and receptor expressions were downregulated in diabetic mice, and TLS nullified this effect. PKRA7 eliminated the impact of TLS on cardiomyocytes. This evidence suggests that TLS rescues DM-induced myocardial function, pyroptosis, and apoptosis, likely via the PK2/PKR pathway.
Highlights
The prevalence of diabetes mellitus (DM) in adults exceeds 10% in China, and European and American countries have rates that are three times higher than that in China; DM has become a major disease threatening human health [1, 2]
Echocardiographic assessment revealed that DM caused a decrease in heart rate (HR), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and the E/A ratio
The remarkable discovery from our present study was that TLS administration alleviated DM-induced cardiac dysfunction, cardiomyocyte apoptosis, and pyroptosis by stimulating the PK2/PKR pathway and increasing autophagy (Figure 10)
Summary
The prevalence of diabetes mellitus (DM) in adults exceeds 10% in China, and European and American countries have rates that are three times higher than that in China; DM has become a major disease threatening human health [1, 2]. The pathogenesis of DCM is relatively complicated, and diabetic dyslipidemia [3], mitochondrial damage [4], oxidative stress [5], myocardial fibrosis [6], apoptosis [7], pyroptosis [8], and autophagy abnormalities [9] are involved in the occurrence and development of DCM. Existing antihyperglycemic treatments alleviate the development of DCM, the results did not meet expectations. The high prevalence rate and poor prognosis of DCM remain problems for clinical medical staff [10, 11]. Studying the pathogenesis of DCM and finding a prevention and treatment strategy are extremely urgent needs
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