Potential Role of Dipeptidyl Peptidase-4 in Regulating Mitochondria and Oxidative Stress in Cardiomyocytes.

Oxidative stress causes mitochondrial damage and bioenergetic dysfunction and inhibits adenosine triphosphate production, contributing to the pathogenesis of cardiac diseases. Dipeptidyl peptidase 4 (DPP4) is primarily a membrane-bound extracellular peptidase that cleaves Xaa-Pro or Xaa-Ala dipeptides from the N terminus of polypeptides. DPP4 inhibitors have been used in patients with diabetes and heart failure; however, they have led to inconsistent results. Although the enzymatic properties of DPP4 have been well studied, the substrate-independent functions of DPP4 have not. In the present study, we knocked down DPP4 in cultured cardiomyocytes to exclude the effects of differential alteration in the substrates and metabolites of DPP4 then compared the response between the knocked-down and wild-type cardiomyocytes during exposure to oxidative stress. H2O2 exposure induced DPP4 expression in both types of cardiomyocytes. However, knocking down DPP4 substantially reduced the loss of cell viability by preserving mitochondrial bioenergy, reducing intracellular reactive oxygen species production, and reducing apoptosis-associated protein expression. These findings demonstrate that inhibiting DPP4 improves the body's defense against oxidative stress by enhancing Nrf2 and PGC-1α signaling and increasing superoxide dismutase and catalase activity. Our results indicate that DPP4 mediates the body's response to oxidative stress in individuals with heart disease.

Caffeic acid ethanolamide induces antifibrosis, anti-inflammatory, and antioxidant effects protects against bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease; its cause is unknown, and it leads to notable health problems. Currently, only two drugs are recommended for IPF treatment. Although these drugs can mitigate lung function decline, neither can improve nor stabilize IPF or the symptoms perceived by patients. Therefore, the development of novel treatment options for pulmonary fibrosis is required. The present study investigated the effects of a novel compound, caffeic acid ethanolamide (CAEA), on human pulmonary fibroblasts and evaluated its potential to mitigate bleomycin-induced pulmonary fibrosis in mice. CAEA inhibited TGF-ß-induced α-SMA and collagen expression in human pulmonary fibroblasts, indicating that CAEA prevents fibroblasts from differentiating into myofibroblasts following TGF-ß exposure. In animal studies, CAEA treatment efficiently suppressed immune cell infiltration and the elevation of TNF-α and IL-6 in bronchoalveolar lavage fluid in mice with bleomycin-induced pulmonary fibrosis. Additionally, CAEA exerted antioxidant effects by recovering the enzymatic activities of oxidant scavengers. CAEA directly inhibited activation of TGF-ß receptors and protected against bleomycin-induced pulmonary fibrosis through inhibition of the TGF-ß/SMAD/CTGF signaling pathway. The protective effect of CAEA was comparable to that of pirfenidone, a clinically available drug. Our findings support the potential of CAEA as a viable method for preventing the progression of pulmonary fibrosis.

A novel caffeic acid derivative prevents renal remodeling after ischemia/reperfusion injury.

Acute kidney disease due to renal ischemia/reperfusion (I/R) is a major clinical problem without effective therapies. The injured tubular epithelial cells may undergo epithelial-mesenchymal transition (EMT). It will loss epithelial phenotypes and express the mesenchymal characteristics. The formation of scar tissue in the interstitial space during renal remodeling is caused by the excessive accumulation of extracellular matrix components and induced fibrosis. This study investigated the effect of caffeic acid ethanolamide (CAEA), a novel caffeic acid derivative, on renal remodeling after injury. The inhibitory role of CAEA on EMT was determined by western blotting, real-time PCR, and immunohistochemistry staining. Treating renal epithelial cells with CAEA in TGF-ß exposed cell culture successfully maintained the content of E-cadherin and inhibited the expression of mesenchymal marker, indicating that CAEA prevented renal epithelial cells undergo EMT after TGF-ß exposure. Unilateral renal I/R were performed in mice to induce renal remodeling models. CAEA can protect against I/R-induced renal remodeling by inhibiting inflammatory reactions and consecutively inhibiting TGF-ß-induced EMT, characterized by the preserved E-cadherin expression and alleviated α-SMA and collagen expression, as well as the alleviated of renal fibrosis. We also revealed that CAEA may exhibits biological activity by targeting TGFBRI. CAEA may antagonize TGF-ß signaling by interacting with TGFBR1, thereby blocking binding between TGF-ß and TGFBR1 and reducing downstream signaling, such as Smad3 phosphorylation. Our data support the administration of CAEA after I/R as a viable method for preventing the progression of acute renal injury to renal fibrosis.

Soluble Dipeptidyl Peptidase-4 Induces Fibroblast Activation Through Proteinase-Activated Receptor-2.

Fibroblasts are the chief secretory cells of the extracellular matrix (ECM) responsible for basal deposition and degradation of the ECM under normal conditions. During stress, fibroblasts undergo continuous activation, which is defined as the differentiation of fibroblasts into myofibroblasts, a cell type with an elevated capacity for secreting ECM proteins. Dipeptidyl peptidase-4 (DPP4) is a ubiquitously expressed transmembrane glycoprotein and exerts effects that are both dependent and independent of its enzymatic activity. DPP4 has been demonstrated to define fibroblast populations in human skin biopsies of systemic sclerosis. Shedding of DPP4 from different tissues into the circulation appears to be involved in the pathogenesis of the diseases. The mechanism underlying soluble DPP4-induced dermal fibrosis has not been clearly determined. The effects of DPP4 on murine 3T3 fibroblasts and human dermal fibroblasts were evaluated by measuring the expression of fibrotic proteins, such as α-SMA and collagen. Soluble DPP4 stimulated the activation of fibroblasts in a dose-dependent manner by activating nuclear factor-kappa B (NF-κB) and suppressor of mothers against decapentaplegic (SMAD) signaling. Blocking proteinase-activated receptor-2 (PAR2) abrogated the DPP4-induced activation of NF-κB and SMAD and expression of fibrosis-associated proteins in fibroblasts. Linagliptin, a clinically available DPP4 inhibitor, was observed to abrogate the soluble DPP4-induced expression of fibrotic proteins. This study demonstrated the mechanism underlying soluble DPP4, which activated NF-κB and SMAD signaling through PAR2, leading to fibroblast activation. Our data extend the current view of soluble DPP4. Elevated levels of circulating soluble DPP4 may contribute to one of the mediators that induce dermal fibrosis in patients.