The goal of this study was to evaluate the intensity of autophagy and ubiquitin-dependent proteolysis processes occurring in myocardium of left ventricle (LV) in subsequent stages of pulmonary arterial hypertension (PAH) to determine mechanisms responsible for LV mass loss in a monocrotaline-induced PAH rat model. LV myocardium samples collected from 32 Wistar rats were analyzed in an early PAH group (n = 8), controls time-paired (n = 8), an end-stage PAH group (n = 8), and their controls (n = 8). Samples were subjected to histological analyses with immunofluorescence staining, autophagy assessment by western blotting, and evaluation of ubiquitin-dependent proteolysis in the LV by immunoprecipitation of ubiquitinated proteins. Echocardiographic, hemodynamic, and heart morphometric parameters were assessed regularly throughout the experiment. Considerable morphological and hemodynamic remodeling of the LV was observed over the course of PAH. The end-stage PAH was associated with significantly impaired LV systolic function and a decrease in LV mass. The LC3B-II expression in the LV was significantly higher in the end-stage PAH group compared to the early PAH group (p = 0.040). The measured LC3B-II/LC3B-I ratios in the end-stage PAH group were significantly elevated compared to the controls (p = 0.039). Immunofluorescence staining showed a significant increase in the abundance of LC3 puncta in the end-stage PAH group compared to the matched controls. There were no statistically significant differences in the levels of expression of all ubiquitinated proteins when comparing both PAH groups and matched controls. Autophagy may be considered as the mechanism behind the LV mass loss at the end stage of PAH.

Vital for growth, proliferation, subsistence, and thermogenesis, autophagy is the biological cascade, which confers defence against aging and various pathologies. Current research has demonstrated de novo activity of autophagy in stimulation of biological events. There exists a significant association between autophagy activation and obesity, encompassing expansion of adipocytes which facilitates β cell activity. The main objective of the manuscript is to enumerate intrinsic role of autophagy in obesity and associated complications. The peer review articles published till date were searched using medical databases like PubMed and MEDLINE for research, primarily in English language. Obesity is characterized by adipocytic hypertrophy and hyperplasia, which leads to imbalance of lipid absorption, free fatty acid release, and mitochondrial activity. Detailed evaluation of obesity progression is necessary for its treatment and related comorbidities. Data collected in regard to etiological sustaining of obesity, has revealed hypothesized energy misbalance and neuro-humoral dysfunction, which is stimulated by autophagy. Autophagy regulates chief salvaging events for protein clustering, excessive triglycerides, and impaired mitochondria which is accompanied by oxidative and genotoxic stress in mammals. Autophagy is a homeostatic event, which regulates biological process by eliminating lethal cells and reprocessing physiological constituents, comprising of proteins and fat. Unquestionably, autophagy impairment is involved in metabolic syndromes, like obesity. According to an individual\'s metabolic outline, autophagy activation is essential for metabolism and activity of the adipose tissue and to retard metabolic syndrome i.e. obesity. The manuscript summarizes the perception of current knowledge on autophagy stimulation and its effect on the obesity.

Currently, most antioxidants do not show any favorable clinical outcomes in reducing myocardial ischemia-reperfusion (I/R) injury, suggesting an urgent need for exploring a new regulator of redox homeostasis in I/R hearts. Here, using heart-specific transgenic (TG) and knockdown (KD) mouse models, tumor susceptibility gene 101 (Tsg101) is defined as a novel cardiac-protector against I/R-triggered oxidative stress. RNA sequencing and bioinformatics data surprisingly reveal that most upregulated genes in Tsg101-TG hearts are transcribed by Nrf2. Accordingly, pharmacological inhibition of Nrf2 offsets Tsg101-elicited cardio-protection. Mechanistically, Tsg101 interacts with SQSTM1/p62 through its PRR domain, and promotes p62 aggregation, leading to recruitment of Keap1 for degradation by autophagosomes and release of Nrf2 to the nucleus. Furthermore, knockout of p62 abrogates Tsg101-induced cardio-protective effects during I/R. Hence, our findings uncover a previously unrecognized role of Tsg101 in the regulation of p62/Keap1/Nrf2 signaling cascades and provide a new strategy for the treatment of ischemic heart disease.