Mechanosensitive cation currents through TRPC6 and Piezo1 channels in human pulmonary arterial endothelial cells.

Mechanosensitive cation channels and Ca2+ influx through these channels play an important role in the regulation of endothelial cell functions. Transient receptor potential canonical channel 6 (TRPC6) is a diacylglycerol-sensitive nonselective cation channel that forms receptor-operated Ca2+ channels in a variety of cell types. Piezo1 is a mechanosensitive cation channel activated by membrane stretch and shear stress in lung endothelial cells. In this study, we report that TRPC6 and Piezo1 channels both contribute to membrane stretch-mediated cation currents and Ca2+ influx or increase in cytosolic-free Ca2+ concentration ([Ca2+]cyt) in human pulmonary arterial endothelial cells (PAECs). The membrane stretch-mediated cation currents and increase in [Ca2+]cyt in human PAECs were significantly decreased by GsMTX4, a blocker of Piezo1 channels, and by BI-749327, a selective blocker of TRPC6 channels. Extracellular application of 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane permeable analog of diacylglycerol, rapidly induced whole cell cation currents and increased [Ca2+]cyt in human PAECs and human embryonic kidney (HEK)-cells transiently transfected with the human TRPC6 gene. Furthermore, membrane stretch with hypo-osmotic or hypotonic solution enhances the cation currents in TRPC6-transfected HEK cells. In HEK cells transfected with the Piezo1 gene, however, OAG had little effect on the cation currents, but membrane stretch significantly enhanced the cation currents. These data indicate that, while both TRPC6 and Piezo1 are involved in generating mechanosensitive cation currents and increases in [Ca2+]cyt in human PAECs undergoing mechanical stimulation, only TRPC6 (but not Piezo1) is sensitive to the second messenger diacylglycerol. Selective blockers of these channels may help develop novel therapies for mechanotransduction-associated pulmonary vascular remodeling in patients with pulmonary arterial hypertension.

Mechanosensitive channel Piezo1 is required for pulmonary artery smooth muscle cell proliferation.

Concentric pulmonary vascular wall thickening due partially to increased pulmonary artery (PA) smooth muscle cell (PASMC) proliferation contributes to elevating pulmonary vascular resistance (PVR) in patients with pulmonary hypertension (PH). Although pulmonary vasoconstriction may be an early contributor to increasing PVR, the transition of contractile PASMCs to proliferative PASMCs may play an important role in the development and progression of pulmonary vascular remodeling in PH. A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) is a trigger for PASMC contraction and proliferation. Here, we report that upregulation of Piezo1, a mechanosensitive cation channel, is involved in the contractile-to-proliferative phenotypic transition of PASMCs and potential development of pulmonary vascular remodeling. By comparing freshly isolated PA (contractile PASMCs) and primary cultured PASMCs (from the same rat) in a growth medium (proliferative PASMCs), we found that Piezo1, Notch2/3, and CaSR protein levels were significantly higher in proliferative PASMCs than in contractile PASMCs. Upregulated Piezo1 was associated with an increase in expression of PCNA, a marker for cell proliferation, whereas downregulation (with siRNA) or inhibition (with GsMTx4) of Piezo1 attenuated PASMC proliferation. Furthermore, Piezo1 in the remodeled PA from rats with experimental PH was upregulated compared with PA from control rats. These data indicate that PASMC contractile-to-proliferative phenotypic transition is associated with the transition or adaptation of membrane channels and receptors. Upregulated Piezo1 may play a critical role in PASMC phenotypic transition and PASMC proliferation. Upregulation of Piezo1 in proliferative PASMCs may likely be required to provide sufficient Ca2+ to assure nuclear/cell division and PASMC proliferation, contributing to the development and progression of pulmonary vascular remodeling in PH.

Trichorrhexis invaginata and ichthyosiform erythroderma in netherton syndrome.

Trichorrhexis invaginata and ichthyosiform erythroderma are pathognomic for Netherton Syndrome.

Comparison of losartan and amlodipine effects on the outcomes of patient with COVID-19 and primary hypertension: A randomised clinical trial.

BACKGROUND: Controversy exists regarding the drug selection in hypertension (HTN) management in patients with COVID-19. This study aimed to compare the effects of losartan and amlodipine in patients with primary HTN and COVID-19. METHODS: In this randomised clinical trial, hospitalised patients with COVID-19 and primary HTN were enrolled in the study. One arm received losartan, 25 mg, twice a day and the other arm received amlodipine, 5 mg per day for 2 weeks. The main outcomes were compare 30-day mortality rate and length of hospital stay. RESULTS: The mean age of patients treated with losartan (N = 41) and amlodipine (N = 39) was 67.3 ± 14.8 and 60.1 ± 17.3 years, respectively (P value = .068). The length of hospital stay in losartan and amlodipine groups was 4.57 ± 2.59 and 7.30 ± 8.70 days, respectively (P value = .085). Also, the length of ICU admission in losartan and amlodipine group was 7.13 ± 5.99 and 7.15 ± 9.95 days, respectively (P value = .994). The 30-day mortality was two and five patients in losartan and amlodipine groups, respectively (P value = .241). CONCLUSIONS: There was no priority in losartan or amlodipine administration in COVID-19 patients with primary HTN in decreasing mortality rate, hospital and ICU length stay. Further studies need to clarify the first-line anti-HTN medications in COVID-19.

Prevalence, Risk Factors and Outcomes Associated with Acute Kidney Injury in Patients Hospitalized for COVID-19: A Comparative Study between Diabetic and Nondiabetic Patients.

BACKGROUND: The risk factors for acute kidney injury (AKI) development in patients with diabetes hospitalized for COVID-19 have not been fully studied yet. In this study, we aimed to estimate the rate of AKI among the hospitalized population with COVID-19 and to identify the risk factors associated with AKI among patients with diabetes. Material and Methods. This retrospective cohort study included 254 patients (127 with diabetes and 127 without diabetes) who were admitted for COVID-19 to a tertiary hospital in Tehran, Iran, between February and May 2020. Clinical characteristics and outcomes, radiological findings, and laboratory data, including data on AKI, hematuria, and proteinuria were recorded and analyzed. RESULTS: Of 254 patients, 142 (55.9%) were male and the mean (± SD) age was 65.7 years (±12.5). In total, 58 patients (22.8%) developed AKI during hospitalization, of whom 36 patients had diabetes (p = 0.04); most patients (74.1%) had stage 1 or 2 AKI. Also, 8 patients (13.8%) required renal replacement therapy (RRT) after developing AKI. Regardless of diabetes status, patients who developed AKI had significantly higher mortality rates compared with patients who did not develop AKI (p = 0.02). Hematuria and proteinuria were observed in 38.1% and 55% of patients, respectively. Multivariate analysis showed that invasive mechanical ventilation, proteinuria, HBA1c level, history of cardiovascular disease, and use of statins were independent risk factors for AKI development in patients with diabetes. CONCLUSION: Results of this study showed that AKI develops in a considerable percentage of patients with COVID-19, especially in those with diabetes, and is significantly associated with mortality.

Targeted anti-inflammatory therapy is a new insight for reducing cardiovascular events: A review from physiology to the clinic.

Despite considerable progressions, cardiovascular disease (CVD) is still one of the major causes of mortality around the world, indicates an important and unmet clinical need. Recently, extensive studies have been performed on the role of inflammatory factors as either a major or surrogate factor in the pathophysiology of CVD. Epidemiological observations suggest the theory of the role of inflammatory mediators in the development of cardiovascular events. This may support the idea that targeted anti-inflammatory therapies, on the background of traditional validated medical therapies, can play a significant role in prevention and even reduction of cardiovascular disorders. Many randomized controlled trials have shown that drugs commonly useful for primary and secondary prevention of CVD have an anti-inflammatory mechanism. Further, many anti-inflammatory drugs are being examined because of their potential to reduce the risk of cardiovascular problems. In this study, we review the process of inflammation in the development of cardiovascular events, both in vivo and clinical evidence in immunotherapy for CVD.

Association of the mean platelet volume and red cell distribution width with dipper and non-dipper blood pressure in prehypertensive non-smokers.

OBJECTIVE: Absence of nocturnal blood pressure (BP) dipping is associated with poor health outcomes, including increased mortality. Non-dipper BP seems to be a predictor of cardiovascular damage in hypertensive patients. The aim of this study was to investigate the association of the mean platelet volume (MPV) and red cell distribution width (RDW) with nocturnal dipping/non dipping status in newly diagnosed and untreated prehypertensive non-smokers, using ambulatory BP monitoring. RESULTS: Twenty-eight patients (15 males) in the dipper group and 24 patients (11 males) in the non-dipper group were evaluated in this study. The age of patients was 41.64 ± 15.01 and 37.96 ± 15.08 years in the dipper and non-dipper groups, respectively. The rate of nocturnal systolic BP drop in the dipper and non-dipper groups was 13.79 ± 3.35% (10.20-22.10) and 5.96 ± 2.87% (1.10-9.30) (P < 0.001), respectively. Also, the mean rate of nocturnal diastolic BP drop in the dipper and non-dipper groups was 17.02 ± 5.09% (10.30-26.90) and 6.19 ± 2.75% (1.20-9.70) (P < 0.001), respectively. RDW and MPV were significantly higher in non-dipper patients than dipper patients (P = 0.001 and P = 0.012, respectively). Bivariate analysis revealed that MPV was inversely correlated with the nocturnal systolic BP drop (P = 0.005, r = - 0.385). Furthermore, RDW was inversely correlated with systolic BP drop (P = 0.019, r = - 0.324).