Enhancement of cardiac angiogenesis in a myocardial infarction rat model using selenium alone and in combination with PTXF: the role of Akt/HIF-1α signaling pathway.

Ischemic heart diseases such as myocardial infarction (MI) are a global health problem and a leading cause of mortality worldwide. Angiogenesis is an important approach for myocardial healing following ischemia. Thus, this study aimed to explore the potential cardiac angiogenic effects of selenium (Se), alone and in combination with the tumor necrosis factor-alpha inhibitor, pentoxifylline (PTXF), via Akt/HIF-1α signaling. MI was induced in rats using two subcutaneous doses of isoprenaline (ISP) at a 24-h interval (150 mg/kg). One week later, rats were orally given Se (150 µg/kg/day), PTXF (50 mg/kg/day), or Se/PTXF combination. ISP-induced myocardial damage was evident by increased HW/TL ratios, ST segment elevation, and increased serum levels of CK-MB, LDH, and troponin-I. ISP increased the cardiac levels of the lipid peroxidation marker MDA; the pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α; and the pro-apoptotic protein Bax and caspase-3. In contrast, the cardiac levels of the antioxidant markers GSH and SOD and the anti-apoptotic marker Bcl-2 were reduced. Furthermore, ISP markedly increased the cardiac levels of p-Akt and HIF-1α proteins and the cardiac gene expression of ANGPT-1, VEGF, and FGF-2. Treatment with Se both alone and in combination with PTXF ameliorated the ISP-induced myocardial damage and further increased cardiac angiogenesis via Akt/HIF-1α signaling. Se/PTXF combined therapy was more beneficial than individual treatments. Our study revealed for the first time the cardiac angiogenic effects of Se both alone and in combination with PTXF in myocardial infarction, suggesting that both may be promising candidates for clinical studies.

Vanillin and pentoxifylline ameliorate isoproterenol-induced myocardial injury in rats via the Akt/HIF-1α/VEGF signaling pathway.

Myocardial infarction (MI) is a major health problem associated with high morbidity and mortality. Recently, angiogenesis has emerged as a novel therapeutic approach against ischemic diseases including MI. Therefore, we aimed to investigate the potential angiogenic effects of vanillin (Van) both alone and in combination with pentoxifylline (PTX), and to examine the molecular mechanisms through which Van and PTX may ameliorate cardiac injury induced in rats including their effects on oxidative stress, inflammation and apoptosis which play a key role in MI pathogenesis. MI was induced in rats using isoproterenol (ISO) (150 mg kg-1, SC, twice at a 24 h interval). Then, rats were treated orally with Van (150 mg kg-1 day-1), PTX (50 mg kg-1 day-1) or Van + PTX combination. ISO-induced cardiac injury was characterized by cardiac hypertrophy, ST-segment elevation and elevated serum levels of troponin-I, creatine kinase-MB and lactate dehydrogenase. Cardiac levels of the antioxidant markers GSH and SOD and the antiapoptotic protein Bcl-2 were decreased. On the other hand, cardiac levels of the oxidative stress marker malonaldehyde, the inflammatory cytokines TNF-α, IL-6 and IL-1ß, the proapoptotic protein Bax, and caspase-3 were increased. Moreover, the cardiac levels of p-Akt and HIF-1α and the mRNA expression levels of the angiogenic genes VEGF, FGF-2 and ANGPT-1 were increased. Treatment with either Van or PTX ameliorated ISO-induced changes and further upregulated Akt/HIF-1α/VEGF signaling. Furthermore, Van + PTX combination was more effective than monotherapy. These findings suggest a novel therapeutic potential of Van and PTX in ameliorating MI through enhancing cardiac angiogenesis and modulating oxidative stress, inflammation and apoptosis.

Potential therapeutic efficacy of pachymic acid in chronic kidney disease induced in rats: role of Wnt/ß-catenin/renin-angiotensin axis.

OBJECTIVES: Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/ß-catenin signalling in CKD. METHODS: CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX. KEY FINDINGS: DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1ß, Wnt1, active ß-catenin/total ß-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy. CONCLUSIONS: These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/ß-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/ß-catenin signalling and its downstream targets.

Inactivation of Wnt/ß-catenin/renin angiotensin axis by tumor necrosis factor-alpha inhibitor, infliximab, ameliorates CKD induced in rats.

Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-α was reported to inhibit klotho, reactivate ß-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-α can regulate Wnt/ß-catenin pathway via klotho in CKD in vivo is not studied yet. We aimed to investigate the impact of IFX on Wnt/ß-catenin pathway in doxorubicin (DOX)-induced nephropathy. Doxorubicin (3.5 mg/kg; i.p., twice weekly for 3 weeks) increased serum cystatin-C, urine albumin/creatinine ratio (UACR), but depleted renal podocin. It markedly increased renal contents of TNF-α, interleukin-6 (IL-6), interleukin-1ß (IL1ß). DOX decreased the renal expression of klotho which in turn increased Wnt1, active ß-catenin/total ß-catenin ratio in renal tissue. Significant increase in renal gene expression of RENIN, ACE, and AT1 was observed. Moreover, renal fibronectin and collagen deposition increased in renal tissue. Treatment with either IFX (5 mg/kg, once; i.p.), losartan (LOS, 10 mg/kg/day, orally) or their combination significantly improved renal function, inhibited inflammatory cytokines and fibrosis. Renal TNF-α was negatively correlated with renal klotho. On the hand, it was positively correlated with renal Wnt1 and active ß-catenin/total ß-catenin ratio. The combined IFX and LOS treatment was the most effective in improving all studied parameters. In conclusion, this study proved, for the first time, the inhibitory effect of IFX on renal Wnt/ß-catenin signaling in DOX-induced nephropathy in vivo by up-regulating renal klotho. Therefore, these results suggest a new role for IFX in chronic kidney disease via targeting renal Wnt/ß-catenin/renin angiotensin axis.