Search

Developmental exposure to environmental pollutants has been shown to promote adverse health outcomes in offspring. Exposure to heavy metals such as arsenic which also has endocrine disrupting activity is being increasingly linked with cancers, diabetes and lately with the metabolic syndrome (MetS). In this work we have assessed the effects of only prenatal arsenic exposure on developmental programming of MetS in offspring. In our study, only prenatal arsenic exposure led to reduced birth weight which was followed by catch-up growth, adiposity, elevated serum triglycerides levels and hyperglycemia in male offspring. Significant adipocytes dysfunction was observed in offspring with increased hypertrophy, insulin resistance, and chronic inflammation in epididymal white adipose tissue. Adipose tissue regulates the metabolic health of individual and its dysfunction resulted in elevated serum levels of metabolism regulating adipokines (Leptin, Resistin) and pro-inflammatory cytokines (PAI-1, TNFα). The progenitor adipose derived stem/stromal cells (AdSCs) from exposed progeny had increased proliferation and adipogenic potential with increased lipid accumulation. We also found increased activation of Akt, ERK1/2 & p38 MAPK molecules in arsenic exposed AdSCs along with increased levels of phospho-Insulin-like growth factor-1 receptor and its upstream activator Insulin-like growth factor-2 (IGF2). Overexpression of IGF2 was found to be due to arsenic mediated DNA hypermethylation at ICR region located − 2kb to -4.4kb upstream of H19 Transcription start site (TSS) which caused reduction in the conserved zinc finger protein (CTCF) occupancy. This further led to persistent activation of AKT & MAPK signaling cascade and enhanced adipogenesis leading to early onset of metabolic syndrome in the offspring.

Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs), inflammation, as well as mitochondrial and metabolic dysregulation, contributes to the development of pulmonary hypertension (PH). Pyrroloquinoline quinone (PQQ), a potent natural antioxidant with anti-diabetic, neuroprotective, and cardioprotective properties, is known to promote mitochondrial biogenesis. However, its effect on cellular proliferation, apoptosis resistance, mitochondrial and metabolic alterations associated with PH remains unexplored. The current study was designed to investigate the effect of PQQ in the treatment of PH. Human pulmonary artery smooth muscle cells (HPASMCs), endothelial cells (PAECs), and primary cultured cardiomyocytes were subjected to hypoxia to induce PH-like phenotype. Furthermore, Sprague Dawley (SD) rats injected with monocrotaline (MCT) (60 mg/kg, SC, once) progressively developed pulmonary hypertension. PQQ treatment (2 mg/kg, PO, for 35 days) attenuated cellular proliferation and promoted apoptosis via a mitochondrial-dependent pathway. Furthermore, PQQ treatment in HPASMCs prevented mitochondrial and metabolic dysfunctions, improved mitochondrial bioenergetics while preserving respiratory complexes, and reduced insulin resistance. In addition, PQQ treatment (preventive and curative) significantly attenuated the increase in right ventricle pressure and hypertrophy as well as reduced endothelial dysfunction and pulmonary artery remodeling in MCT-treated rats. PQQ also prevented cardiac fibrosis and improved cardiac functions as well as reduced inflammation in MCT-treated rats. Altogether, the above findings demonstrate that PQQ can attenuate mitochondrial as well as metabolic abnormalities in PASMCs and also prevent the development of PH in MCT treated rats; hence PQQ may act as a potential therapeutic agent for the treatment of PH.