The role of carbonic anhydrase III and autophagy in type 2 diabetes with cardio-cerebrovascular disease

Abstract

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases among the elderly people. The T2DM increases the risk of cardio-cerebrovascular disease (CCD), and the main pathological change of the CCD is atherosclerosis (AS). Meanwhile, the carbonic anhydrases (CAs) are involved in the formation and progression of plaques in AS. However, the exact physiological mechanism of carbonic anhydrase III (CAIII) has not been clear yet, and there are also no correlation study between CAIII protein and T2DM with CCD. The 8-week old diabetic mice (db/db−/− mice) and wild-type mice (wt mice) were feed by a normal diet till 32 weeks, and detected the carotid artery vascular opening angle using the method of biomechanics; The changes of cerebral cortex and myocardium were watched by the ultrastructure, and the autophagy were observed by electron microscope; The tissue structure, inflammation and cell injury were observed by Hematoxylin and eosin (HE) staining; The apoptosis of cells were observed by TUNEL staining; The protein levels of CAIII, IL-17, p53 were detected by immunohistochemical and Western Blot, and the Beclin-1, LC3, NF-κB were detected by Western Blot. All statistical analysis is performed using PRISM software. Compared with wt mice, db/db−/− mice’ carotid artery open angle increased significantly. Electron microscope results indicated that autophagy in db/db−/− mice cerebral cortex and heart tissue decreased and intracellular organelle ultrastructure were damaged. HE staining indicated that, db/db−/− mice’ cerebral cortex and heart tissue stained lighter, inflammatory cells infiltration, cell edema were obvious, myocardial fibers were disorder, and myocardial cells showed different degrees of degeneration. Compared with wt mice, TUNEL staining showed that there was obviously increase in db/db−/− mice cortex and heart tissue cell apoptosis. The results of immunohistochemistry and Western Blot indicated that CAIII, Beclin-1 and LC3II/I expression levels conspicuously decreased in cortex and heart tissue of db/db−/− mice, and the expression level of IL-17, NF-κB and p53 obviously increased. The carotid artery’ vascular stiffness was increased and which was probably related with formation of AS in diabetic mice. And the autophagy participated in the occurrence and development of diabetic CCD. CAIII protein might somehow be involved in the regulation of autophagy probably through affecting cell apoptosis and inflammation, but the underlying mechanism remains to be further studied.

S‐9‐PAHSA's neuroprotective effect mediated by CAIII suppresses apoptosis and oxidative stress in a mouse model of type 2 diabetes

“…to have several similarities to S-9-PAHSA, such as an ability to combat oxidative stress and a relationship with diabetes. 29,51 CAIII plays a crucial role in reducing oxidative stress and also appears to be essential for cognition, with evidence that it is downregulated in the cortex and myocardium of diabetic mouse models. 27,29 Based on these results, we speculated that CAIII may be involved in the anti-oxidative stress and anti-apoptotic effects of S-9-PAHSA.…”

“…As an enzyme with antioxidant effects, CAIII has been shown to have several similarities to S‐9‐PAHSA, such as an ability to combat oxidative stress and a relationship with diabetes 29,51 . CAIII plays a crucial role in reducing oxidative stress and also appears to be essential for cognition, with evidence that it is downregulated in the cortex and myocardium of diabetic mouse models 27,29 .…”

“…Our previous study demonstrated that CAIII was downregulated in the myocardium and cortex in mouse models of T2DM, suggesting its involvement in the pathological progression of the disorder and its complications. 29 However, the exact molecular mechanism of these effects still requires further investigation.…”

“…Taken together, these findings indicate that oxidative stress is involved in the neuronal pathology of T2DM and that S-9-PAHSA may play a key role in neuroprotection as well as influencing glucolipid metabolism. 28,29 Considering the similar biological activity of CAIII and PAHSA on anti-oxidative stress, and cognitive function in T2DM, it is possible that CAIII may be involved in the protective effect of S-9-PAHSA. However, evidence to confirm this relationship and its specific mechanisms requires further study.…”

Emerging biomarkers for the detection of cardiovascular diseases

“…This enzyme possesses antioxidative properties and is critical for maintaining intracellular pH homeostasis. Given that high blood CA-III levels, often in conjunction with other muscle-specific proteins, are commonly used to diagnose overall muscle injury, it seemed worthwhile to review current CA-III investigations [33].…”