SGLT2 inhibitor empagliflozin alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease.

Recent evidence shows a close link between Parkinson's disease (PD) and cardiac dysfunction with limited treatment options. Mitophagy plays a crucial role in the control of mitochondrial quantity, metabolic reprogramming and cell differentiation. Mutation of the mitophagy protein Parkin is directly associated with the onset of PD. Parkin-independent receptor-mediated mitophagy is also documented such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and FUN14 domain containing 1 (FUNDC1) for receptor-mediated mitophagy. In this study we investigated cardiac function and mitophagy including FUNDC1 in PD patients and mouse models, and evaluated the therapeutic potential of a SGLT2 inhibitor empagliflozin. MPTP-induced PD model was established. PD patients and MPTP mice not only displayed pronounced motor defects, but also low plasma FUNDC1 levels, as well as cardiac ultrastructural and geometric anomalies (cardiac atrophy, interstitial fibrosis), functional anomalies (reduced E/A ratio, fractional shortening, ejection fraction, cardiomyocyte contraction) and mitochondrial injury (ultrastructural damage, UCP2, PGC1α, elevated mitochondrial Ca2+ uptake proteins MCU and VDAC1, and mitochondrial apoptotic protein calpain), dampened autophagy, FUNDC1 mitophagy and apoptosis. By Gene set enrichment analysis (GSEA), we found overtly altered glucose transmembrane transport in the midbrains of MPTP-treated mice. Intriguingly, administration of SGLT2 inhibitor empagliflozin (10 mg/kg, i.p., twice per week for 2 weeks) in MPTP-treated mice significantly ameliorated myocardial anomalies (with exception of VDAC1), but did not reconcile the motor defects or plasma FUNDC1. FUNDC1 global knockout (FUNDC1-/- mice) did not elicit any phenotype on cardiac geometry or function in the absence or presence of MPTP insult, but it nullified empagliflozin-caused cardioprotection against MPTP-induced cardiac anomalies including remodeling (atrophy and fibrosis), contractile dysfunction, Ca2+ homeostasis, mitochondrial (including MCU, mitochondrial Ca2+ overload, calpain, PARP1) and apoptotic anomalies. In neonatal and adult cardiomyocytes, treatment with PD neurotoxin preformed fibrils of α-synuclein (PFF) caused cytochrome c release and cardiomyocyte mechanical defects. These effects were mitigated by empagliflozin (10 µM) or MCU inhibitor Ru360 (10 µM). MCU activator kaempferol (10 µM) or calpain activator dibucaine (500 µM) nullified the empagliflozin-induced beneficial effects. These results suggest that empagliflozin protects against PD-induced cardiac anomalies, likely through FUNDC1-mediated regulation of mitochondrial integrity.

Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer's disease via inhibition of ACSL4-dependent ferroptosis.

Alzheimer's disease (AD) is associated with high incidence of cardiovascular events but the mechanism remains elusive. Our previous study reveals a tight correlation between cardiac dysfunction and low mitochondrial aldehyde dehydrogenase (ALDH2) activity in elderly AD patients. In the present study we investigated the effect of ALDH2 overexpression on cardiac function in APP/PS1 mouse model of AD. Global ALDH2 transgenic mice were crossed with APP/PS1 mutant mice to generate the ALDH2-APP/PS1 mutant mice. Cognitive function, cardiac contractile, and morphological properties were assessed. We showed that APP/PS1 mice displayed significant cognitive deficit in Morris water maze test, myocardial ultrastructural, geometric (cardiac atrophy, interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies along with oxidative stress, apoptosis, and inflammation in myocardium. ALDH2 transgene significantly attenuated or mitigated these anomalies. We also noted the markedly elevated levels of lipid peroxidation, the essential lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4), the transcriptional regulator for ACLS4 special protein 1 (SP1) and ferroptosis, evidenced by elevated NCOA4, decreased GPx4, and SLC7A11 in myocardium of APP/PS1 mutant mice; these effects were nullified by ALDH2 transgene. In cardiomyocytes isolated from WT mice and in H9C2 myoblasts in vitro, application of Aß (20 µM) decreased cell survival, compromised cardiomyocyte contractile function, and induced lipid peroxidation; ALDH2 transgene or activator Alda-1 rescued Aß-induced deteriorating effects. ALDH2-induced protection against Aß-induced lipid peroxidation was mimicked by the SP1 inhibitor tolfenamic acid (TA) or the ACSL4 inhibitor triacsin C (TC), and mitigated by the lipid peroxidation inducer 5-hydroxyeicosatetraenoic acid (5-HETE) or the ferroptosis inducer erastin. These results demonstrate an essential role for ALDH2 in AD-induced cardiac anomalies through regulation of lipid peroxidation and ferroptosis.

Ischemic post-conditioning attenuates renal ischemic reperfusion injury via down-regulation of toll-like receptor 4 in diabetic rats.

BACKGROUND: Ischemia/reperfusion (I/R) injury, which is commonly seen in the field of renal surgery or transplantation, is a major cause of acute renal failure (ARF). The ischemic ARF in diabetic rats is much more severe than that in the normal rats exposed to as same ischemic time. Ischemic post-conditioning (IPO) is a phenomenon by which intermittent interruptions of blood flow in the early phase of reperfusion can protect organs from I/R injury. To determine whether the renal protection effect of IPO mediates by toll-like receptor 4 (TLR4) signaling pathway in diabetic rats. METHODS: Streptozotocin-induced diabetic rats were randomly divided into three groups: sham operation group, I/R group, and IPO group. Except sham operation group, rats were subjected to 30 min of renal ischemia, both with and without treatment with IPO, then reperfusion 24 h. Light microscope and transmission electronic microscope were used to observe structural changes of renal tubule. RT-PCR was used to measure TLR4 and tumor necrosis factor-alpha (TNF-α) mRNA expression level, renal TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein expression was detected by Western blot. RESULTS: The results demonstrated that IPO markedly decreased renal ischemic injury caused by I/R and inhibited the proinflammatory expression levels of TLR4, TNF-α, and NF-κB, all of which up-regulated by I/R in diabetic rats. CONCLUSION: Taken together, our results suggest that proper IPO may have protective effect on the ischemic injury mediated by renal I/R, which might be associated with inhibition of TLR4 signaling pathway in diabetic rats.

[Increased expressions of leptin and its receptor in the epididymis of varicocele model rats and their implications].

OBJECTIVE: To investigate the expressions of leptin and its receptor in the epididymis of experimental varicocele (EV) rats. METHODS: Forty male Sprague-Dawley rats were randomly divided into four groups: 4-week EV (n = 12), 8-week EV (n = 12), 4-week control (n = 8), and 8-week control (n = 8). EV models were established by partial ligation of the left renal vein. The expressions of leptin and its receptor in the rat epididymis were measured by immunohistochemistry, and their mRNA expressions determined by real-time quantitative PCR. RESULTS: The expressions of leptin and its receptor in the epididymis were significantly higher in the 4- and 8-week EV groups than in the 4- and 8-week control groups (P < 0.01), with no significant difference between the two EV groups (P > 0.05). So were their mRNA expressions in the former two than in the latter two groups (P < 0.01), with no significant difference between the former two (P > 0.05). CONCLUSION: The expressions of leptin and its receptor are markedly increased in the epididymis of varicocele rats. Leptin may be involved in the mechanisms of varicocele inducing male infertility.

Effects of artery-ligating and artery-preserving varicocelectomy on ipsilateral epididymis of varicocele-induced rats.

OBJECTIVES: To investigate the effects of artery-ligating varicocelectomy (ALV) and artery-preserving varicocelectomy (APV) on the ipsilateral epididymis of varicocele-induced rats. METHODS: A total of 50 adolescent male rats were randomly divided into the 4 groups: control group (n = 8), experimental varicocele (EV) without treatment (EV group, n = 14), EV with ALV (ALV group, n = 14), and EV with APV (APV group, n = 14). The EV was induced by partial ligation of the left renal vein. ALV was performed by total ligation of the left internal spermatic artery and vein. APV was performed by ligation of the left internal spermatic vein only. The microstructure, epithelial ultrastructure, sialic acid and carnitine concentration, and epithelial apoptotic index of the left epididymis were measured. RESULTS: Microstructural and ultrastructural abnormalities of the left epididymis were observed in the EV group and especially in the ALV group. Both the mean epididymal tubular diameter and the concentration of sialic acid, carnitine gradually decreased or increased from the control group to the EV group then to the ALV group (P < .05). However, the epithelial apoptotic index orderly increased for the control group, EV group, and ALV group (P < .05). Furthermore, no significant difference was found between the control and APV groups for these parameters (P > .05). CONCLUSIONS: Varicocele was demonstrated to cause lesions of the ipsilateral epididymis. APV was able to repair the lesions; however, ALV led to additional lesions.