The pathophysiology of pulmonary hypertension (PH) and heart failure (HF) includes fibrogenic remodeling associated with the loss of pulmonary arterial (PA) and cardiac compliance. We and others have previously identified transglutaminase 2 (TG2) as a participant in adverse fibrogenic remodeling. However, little is known about the biologic mechanisms that regulate TG2 function. We examined physiological mouse models of experimental PH, HF, and type 1 diabetes that are associated with altered glucose metabolism/glycolysis and report here that TG2 expression and activity are elevated in pulmonary and cardiac tissues under all these conditions. We additionally used PA adventitial fibroblasts to test the hypothesis that TG2 is an intermediary between enhanced tissue glycolysis and fibrogenesis. Our in vitro results show that glycolytic enzymes and TG2 are upregulated in fibroblasts exposed to high glucose, which stimulates cellular glycolysis as measured by Seahorse analysis. We examined the relationship of TG2 to a terminal glycolytic enzyme, pyruvate kinase M2 (PKM2), and found that PKM2 regulates glucose‐induced TG2 expression and activity as well as fibrogenesis. Our studies further show that TG2 inhibition blocks glucose‐induced fibrogenesis and cell proliferation. Our findings support a novel role for glycolysis‐mediated TG2 induction and tissue fibrosis associated with experimental PH, HF, and hyperglycemia.

Diastolic dysfunction of the heart and decreased compliance of the vasculature and lungs (i.e., increased organ tissue stiffness) are known features of obesity and the metabolic syndrome. Similarly, cardiac diastolic dysfunction is associated with aging. Elevation of the enzyme transglutaminase 2 (TG2) leads to protein cross-linking and enhanced collagen synthesis and participates as a candidate pathway for development of tissue stiffness. With these observations in mind we hypothesized that TG2 may be elevated in tissues of a rat model of obesity/metabolic syndrome (the ZSF 1 rat) and a mouse model of aging, i.e., the senescent SAMP8 mouse. In the experiments reported here, TG2 expression and activity were found for the first time to be spontaneously elevated in organs from both the ZSF1 rat and the SAMP8 mouse. These observations are consistent with a hypothesis that a TG2-related pathway may participate in the known tissue stiffness associated with cardiac diastolic dysfunction in these two rodent models. The potential TG2 pathway needs better correlation with physiologic dysfunction and may eventually provide novel therapeutic insights to improve tissue compliance.

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Background Coronavirus disease 2019 (Covid-19) is associated with spontaneous pneumomediastinum (SPM) predominantly in those after positive pressure ventilation (PPV) support. Additionally, many cases of venous thromboembolism (VTE) in COVID-19 patients were described. Our case is the first to describe SPM and VTE present on admission in a patient with Covid –19 pneumonia. Case report A 53-year-old man presented to the hospital with escalating dyspnea. Two weeks prior to this visit, he had been evaluated in an ambulatory setting and was started on antibiotics and systemic steroids. In the hospital, this patient was found to be in acute hypoxic respiratory failure and was placed on noninvasive PPV. Diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) test from nasopharyngeal swab specimen. Chest computed tomography (CT) scan revealed multi-lobar pulmonary emboli (PE) and subcutaneous emphysema with pneumomediastinum. The patient was managed conservatively. He never required closed invasive mechanical ventilation. Subsequent serial imaging displayed the resolution of SPM. Conclusion The association between VTE and COVID-19 has been established. This report brings attention to SPM as an additional important complication of COVID-19, even in patients without pre-existing predisposing pathology or exposure to PPV.

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