TRPC6, a Therapeutic Target for Pulmonary Hypertension

Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Pulmonary vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and pulmonary arterial remodeling due to PASMC proliferation are causes for increased pulmonary vascular resistance in patients with PAH. We and others observed upregulation of TRPC6 channels in PASMC from patients with PAH. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while Ca2+-dependent activation of PI3K/AKT/mTOR pathway is pivotal for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 blocker has yet been developed and tested for treatment of PAH. We sought to investigate whether block of receptor-operated Ca2+ channels or TRPC6 can reverse established PH in mice via inhibiting Ca2+-dependent activation of AKT/mTOR signaling. Here we report that intrapulmonary application of 2-aminoethyl diphenyl borniate (2-APB), a non-selective blocker of cation channels or BI-749237, a selective blocker of TRPC6, significantly and reversibly inhibited acute hypoxic pulmonary vasoconstriction. Intraperitoneal injection of 2-APB significantly attenuated the development of PH and partially reversed established PH. Oral gavage of the selective TRPC6 blocker BI-749237 reversed established PH by 50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749237 both inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMC. These results indicates that the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH. BI-749237, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH.

Circ-Calm4 Regulates Hypoxia-Induced Pulmonary Artery Smooth Muscle Autophagy by Binding Purb

Pulmonary hypertension (PH) is a serious and fatal disease characterized by pulmonary vasoconstriction and pulmonary vascular remodeling. The excessive autophagy of pulmonary artery smooth muscle cells (PASMCs) is one of the important factors of pulmonary vascular remodeling. A number of studies have shown that circular RNA (circRNA) can participate in the onset of PH. Our previous studies have shown that circRNA calmodulin 4 (circ-calm4) is involved in the progression of hypoxic PH. However, the role of circ-calm4 on regulation of hypoxic PH autophagy has not been reported. In this study, we demonstrated for the first time that hypoxia-mediated upregulated circ-calm4 expression has a key regulatory effect on autophagy in hypoxia-induced PASMCs and hypoxic PH mouse models. Knockdown of circ-calm4 both in vivo and in vitro can inhibit the autophagy in PASMCs induced by hypoxia. We also performed bioinformatics predictions and conducted experiments to verify that circ-calm4 bound to the purine-rich binding protein (Purb) to promote its expression in the nucleus, thereby initiating the transcription of autophagy-related protein Beclin1. Interestingly, we found that Beclin1 transcription initiated by Purb was accompanied by a modification of Beclin1 super-enhancer to improve transcription activity and efficiency. Overall, our results confirm that the circ-calm4/Purb/Beclin1 signal axis is involved in the occurrence of hypoxia-induced PASMCs autophagy, and the novel regulatory mechanisms and signals transduction pathways in PASMC autophagy induced by hypoxia.

The influence of hemoconcentration on hypoxic pulmonary vasoconstriction in acute, prolonged, and lifelong hypoxemia

Red blood cell concentration influences the pulmonary vasculature via direct frictional force and vasoactive signaling, but whether the magnitude of the response is modified with duration of exposure is not known. By assessing the pulmonary vascular response to hemodilution in acute normobaric and prolonged hypobaric hypoxia in lowlanders and lifelong hypobaric hypoxemia in Andean natives, we demonstrated that a reduction in red cell concentration augments the vasoconstrictive effects of hypoxia in lowlanders. In high-altitude natives, hemodilution lowered pulmonary vascular resistance, but a compensatory increase in cardiac output following hemodilution rendered PASP unchanged.

Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a serious complication of severe systemic or local pulmonary inflammation, such as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ARDS is characterised by diffuse alveolar damage that leads to protein-rich pulmonary oedema, local alveolar hypoventilation and atelectasis. Inadequate perfusion of these areas is the main cause of hypoxaemia in ARDS. High perfusion in relation to ventilation (V/Q<1) and shunting (V/Q=0) is not only caused by impaired hypoxic pulmonary vasoconstriction but also redistribution of perfusion from obstructed lung vessels. Rebalancing the pulmonary vascular tone is a therapeutic challenge. Previous clinical trials on inhaled vasodilators (nitric oxide and prostacyclin) to enhance perfusion to high V/Q areas showed beneficial effects on hypoxaemia but not on mortality. However, specific patient populations with pulmonary hypertension may profit from treatment with inhaled vasodilators. Novel treatment targets to decrease perfusion in low V/Q areas include epoxyeicosatrienoic acids and specific leukotriene receptors. Still, lung protective ventilation and prone positioning are the best available standard of care. This review focuses on disturbed perfusion in ARDS and aims to provide basic scientists and clinicians with an overview of the vascular alterations and mechanisms of V/Q mismatch, current therapeutic strategies, and experimental approaches.

Analysis of flow resistance in the pulmonary arterial circulation: Implications for hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) plays an essential role in distributing blood in the lung to enhance ventilation-perfusion matching and blood oxygenation. In this study, a theoretical model of the pulmonary vasculature is used to predict the effects of vasoconstriction over specified ranges of vessel diameters on pulmonary vascular resistance (PVR). The model is used to evaluate the ability of hypothesized mechanisms of HPV to account for observed levels of PVR elevation during hypoxia. The vascular structure from pulmonary arteries to capillaries is represented using scaling laws. Vessel segments are modeled as resistive elements and blood flow rates are computed from physical principles. Direct vascular responses to intravascular oxygen levels have been proposed as a mechanism of HPV. In the lung, significant changes in oxygen level occur only in vessels less than 60 μm in diameter. The model shows that observed levels of hypoxic vasoconstriction in these vessels alone cannot account for the elevation of PVR associated with HPV. However, the elevation in PVR associated with HPV can be accounted for if larger upstream vessels also constrict. These results imply that upstream signaling by conducted responses to engage constriction of arterioles plays an essential role in the elevation of PVR during HPV.

COVID-19 with rapid progression to hypoxemia likely due to imbalance between ventilation and blood flow: A case report

We experienced a case of COVID-19 with hypoxia, which was presumed to be due to the development of ventilation and blood flow imbalance by pulmonary intravascular coagulopathy or hypoxic pulmonary vasoconstriction. Early, short-term combination therapy with remdesivir, nafamostat mesilate and low-dose dexamethasone was extremely effective.

Pulmonary Hypertension - A Distinct Perspective

In this review, we have discussed pulmonary hypertension including definition, classification, pathophysiology, epidemiology, diagnosis and treatment of each class of PH as per latest available data and guidelines. Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure of ≥ 20 mmHg at rest. The clinical classification of pulmonary hypertension (as per world health organization) includes five different classes constructed on the basis of clinical causes of pulmonary hypertension. The main pathophysiology involved in the development of pulmonary hypertension of all types is prolonged pulmonary vasoconstriction caused by multiple factors which ultimately leads to pulmonary vascular remodelling (structural as well as functional). The primary treatment of pulmonary hypertension comprises of correction/control of underlying cause of pulmonary hypertension. The prevalence of pulmonary hypertension is increasing in developed as well as developing countries and thus its awareness is important for timely diagnosis and management of this chronic condition. The main aim of our review is to provide all the necessary information regarding pulmonary hypertension in one document. KEYWORDS Pulmonary Hypertension, Chronic Thromboembolism, Left Heart Disease, Lung Disease, Pulmonary Arterial Hypertension