RESUMEN
Rho kinase (ROCK) is implicated in the development of pulmonary arterial hypertension (PAH) in which abnormal pulmonary vascular smooth muscle (VSM) contractility and remodeling lead to right heart failure. Pharmacologic ROCK inhibitors block experimental pulmonary hypertension (PH) development in rodents but can have off-target effects and do not distinguish between the two ROCK forms, ROCK1 and ROCK2, encoded by separate genes. An earlier study using gene knock out (KO) in mice indicated that VSM ROCK2 is required for experimental PH development, but the role of ROCK1 is not well understood. Here we investigated the in vivo role of ROCK1 in PH development by generating a VSM-targeted homozygous ROCK1 gene KO mouse strain. Adult control mice exposed to Sugen5416 (Su)/hypoxia treatment to induce PH had significantly increased right ventricular systolic pressures (RVSP) and RV hypertrophy versus normoxic controls. In contrast, Su/hypoxia-exposed VSM ROCK1 KO mice did not exhibit significant RVSP elevation, and RV hypertrophy was blunted. Su/hypoxia-induced pulmonary small vessel muscularization was similarly elevated in both control and VSM ROCK1 KO animals. siRNA-mediated ROCK1 knock-down (KD) in human PAH pulmonary arterial SM cells (PASMC) did not affect cell growth. However, ROCK1 KD led to reduced AKT and MYPT1 signaling in serotonin-treated PAH PASMC. The findings suggest that like VSM ROCK2, VSM ROCK1 actively contributes to PH development, but in distinction acts via nonproliferative pathways to promote hypoxemia, and thus may be a distinct therapeutic target in PH.
Asunto(s)
Hipertensión Arterial Pulmonar , Quinasas Asociadas a rho , Animales , Hipertrofia Ventricular Derecha/genética , Hipoxia/complicaciones , Ratones , Ratones Noqueados , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/metabolismo , Hipertensión Arterial Pulmonar/genética , Arteria Pulmonar/metabolismo , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/fisiologíaRESUMEN
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.
Asunto(s)
Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Regulación Enzimológica de la Expresión Génica , Glucólisis , Hipertensión Pulmonar/metabolismo , Transglutaminasas/genética , Transglutaminasas/metabolismo , Animales , Proteínas Portadoras/metabolismo , Proliferación Celular , Fibroblastos/metabolismo , Glucosa/metabolismo , Humanos , Hiperglucemia/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína Glutamina Gamma Glutamiltransferasa 2 , Arteria Pulmonar/metabolismo , Piruvato Quinasa/metabolismo , Transducción de Señal , Hormonas Tiroideas/metabolismo , Regulación hacia Arriba , Proteínas de Unión a Hormona TiroideRESUMEN
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.
RESUMEN
BACKGROUND We present a case of a 24-year-old woman with type 1- diabetes mellitus who developed necrotizing fasciitis (NF) due to Streptococcus agalactiae after a recent colposcopy. Literature review suggests this as the first case to be reported. CASE REPORT The patient initially presented to the emergency department (ED) with right lower neck pain and spasm of the right sternocleidomastoid muscle (SCM), with decreased range of motion. She was diagnosed with torticollis and was sent home on a nonsteroidal anti-inflammatory drug and spasmolytic. She returned 5 days later because of a lack of response. Magnetic resonance imaging of her neck revealed edema and inflammatory changes in the distal portion of her right SCM; an oral-systemic steroid was added to her treatment. However, she presented to the ED 3 days after her second visit with worsening symptoms. Her complaints of severe pain involving the right chest wall, development of fever, and the findings on imaging studies prompted the diagnosis of necrotizing soft-tissue infection and NF. She promptly underwent successful surgical debridement. Tissue cultures grew abundant Streptococcus agalactiae. Her antibiotics were readjusted and she was discharged to rehabilitation. Retrospective analysis of the case was notable for colposcopy with cervical biopsy and endocervical curettage for chronic cervicitis and low-grade squamous intraepithelial lesion within a week of her first ED visit. CONCLUSIONS NF caused by Streptococcus agalactiae should be suspected in patients who have had recent genitourinary/gastrointestinal procedures.
Asunto(s)
Colposcopía , Legrado , Fascitis Necrotizante/microbiología , Complicaciones Posoperatorias , Infecciones de los Tejidos Blandos/microbiología , Infecciones Estreptocócicas/diagnóstico , Diabetes Mellitus Tipo 1 , Femenino , Humanos , Lesiones Intraepiteliales Escamosas de Cuello Uterino/cirugía , Streptococcus agalactiae , Adulto JovenRESUMEN
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.