A New Hypothetical Concept in Metabolic Understanding of Cardiac Fibrosis: Glycolysis Combined with TGF-ß and KLF5 Signaling.

The accumulation of fibrosis in cardiac tissues is one of the leading causes of heart failure. The principal cellular effectors in cardiac fibrosis are activated fibroblasts and myofibroblasts, which serve as the primary source of matrix proteins. TGF-ß signaling pathways play a prominent role in cardiac fibrosis. The control of TGF-ß by KLF5 in cardiac fibrosis has been demonstrated for modulating cardiovascular remodeling. Since the expression of KLF5 is reduced, the accumulation of fibrosis diminishes. Because the molecular mechanism of fibrosis is still being explored, there are currently few options for effectively reducing or reversing it. Studying metabolic alterations is considered an essential process that supports the explanation of fibrosis in a variety of organs and especially the glycolysis alteration in the heart. However, the interplay among the main factors involved in fibrosis pathogenesis, namely TGF-ß, KLF5, and the metabolic process in glycolysis, is still indistinct. In this review, we explain what we know about cardiac fibroblasts and how they could help with heart repair. Moreover, we hypothesize and summarize the knowledge trend on the molecular mechanism of TGF-ß, KLF5, the role of the glycolysis pathway in fibrosis, and present the future therapy of cardiac fibrosis. These studies may target therapies that could become important strategies for fibrosis reduction in the future.

Inhibition of the canonical Wnt signaling pathway by a ß-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis.

In heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes ß-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, ß-MHC, and ß-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/ß-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

Antiviral action of the antimicrobial peptide ALFPm3 from Penaeus monodon against white spot syndrome virus.

The anti-lipopolysaccharide factor isoform 3 (ALFPm3), the antimicrobial peptide from Penaeus monodon, possesses antibacterial and antiviral activities. Although the mechanism of action of ALFPm3 against bacteria has been revealed but its antiviral mechanism is still unclear. To further study how the ALFPm3 exhibits antiviral activity against the enveloped virus, white spot syndrome virus (WSSV), the ALFPm3-interacting proteins from WSSV were sought and identified five ALFPm3-interacting proteins, WSSV186, WSSV189, WSSV395, WSSV458, and WSSV471. Only the interaction between ALFPm3 and WSSV189, however, has been confirmed to be involved in anti-WSSV activity of ALFPm3. Herein, the interactions between ALFPm3 and rWSSV186, rWSSV395, rWSSV458, or rWSSV471 were further analyzed and confirmed by in vitro pull-down assay. Western blot analysis and immunoelectron microscopy showed that the uncharacterized proteins, WSSV186 and WSSV471, were nucleocapsid and envelope proteins, respectively. The decrease of shrimp survival after injection the shrimp with mixtures of each rWSSV protein, rALFPm3 and WSSV as compared to those injected with rALFPm3-neutralizing WSSV was clearly observed indicating that all rWSSV proteins could interfere with the neutralization effect of rALFPm3 on WSSV similar to that reported previously for WSSV189. Morphological change on WSSV after incubation with rALFPm3 was observed by TEM. The lysed WSSV virions were clearly observed where both viral envelope and nucleocapsid were dismantled. The results lead to the conclusion that the ALFPm3 displays direct effect on the viral structural proteins resulting in destabilization and breaking up of WSSV virions.

Anti-lipopolysaccharide factor isoform 3 from Penaeus monodon (ALFPm3) exhibits antiviral activity by interacting with WSSV structural proteins.

In innate immunity, antimicrobial peptides (AMPs) play a vital role in combating microbial pathogens. Among the AMPs identified in Penaeus monodon, only anti-lipopolysaccharide factor isoform 3 (ALFPm3) has been reported to exhibit activity against white spot syndrome virus (WSSV). However, the mechanism(s) involved are still not clear. In the present study, ALFPm3-interacting proteins were screened for from a WSSV library using the yeast two-hybrid screening system, revealing the five potential ALFPm3-interacting proteins of WSSV186, WSSV189, WSSV395, WSSV458 and WSSV471. Temporal transcriptional analysis in WSSV-infected P. monodon revealed that all five of these WSSV gene transcripts were expressed in the late phase of infection (24h and 48h post-infection). Of these, WSSV189 that was previously identified as a structural protein, was selected for further analysis and was shown to be an enveloped protein by Western blot and immunoelectron microscopy analyses. The in vitro pull-down assay using recombinant WSSV189 (rWSSV189) protein as bait confirmed the interaction between ALFPm3 and WSSV189 proteins. Moreover, pre-incubation of rWSSV189 protein with rALFPm3 protein interfered with the latter's neutralization effect on WSSV in vivo, as shown by the increased cumulative mortality of shrimp injected with WSSV following prior treatment with pre-incubated rWSSV189 and rALFPm3 proteins compared to that in shrimp pre-treated with rALFPm3 protein. Thus, ALFPm3 likely performs its anti-WSSV action by binding to the envelope protein WSSV189 and possibly other WSSV structural proteins.