01Mar/18

How PTEN May Play A Role In Vascular Disease Pathogenesis

How PTEN May Play A Role In Vascular Disease Pathogenesis Blood Vessels & Smooth Muscle Cells Vessels are the pipeline for transporting blood throughout the body. Blood, in turn, carries oxygen, nutrients, water, and other chemicals to tissues and organs throughout the body. The blood vessel is comprised of three main layers, the tunica intima, the tunica media, and the tunica adventitia. All three layers play a unique role in both physiological homeostasis and in pathological conditions. In this post, we will briefly focus on the role that the key constituents of the tunica media layer, the smooth muscle cells (SMCs), play in vascular disease pathogenesis.… Read More...
05Sep/17

Reactive Oxygen and Nitrogen Species in Pulmonary Hypertension

  In pulmonary hypertension, there is pathological remodeling of the blood vessels due to a pathological hypertensive environment within the vasculature. This hypertensive environment influences how all cells of the vasculature (endothelial cells and smooth muscle cells), as well as fibroblasts and immune cells behave. The environment typically activates fibroblasts and immune cells, causes de-differentiation in smooth muscle cells, induces the contractile phenotype in smooth muscle cells, and may even pushes endothelial cells to failure. How this pathological hypertensive environment occurs is unknown. For example, it could arise from underlying inflammation, from hypoxia, or an apoptosis process gone haywire… There are many theories.… Read More...
10Aug/17

Antioxidants and Reactive Oxygen Species in PH – Do Antioxidants Help or Hurt PH?

While it may not be the cause, evidence from several studies that supports the fact that increased oxidative stress and reactive oxygen species (ROS) together with decreased antioxidant activity can contribute to enhanced pulmonary vasoconstriction, vascular remodeling, and right heart dysfunction in pulmonary hypertension. Despite this evidence however, it is still unknown whether or not an oxidant/antioxidant imbalance contributes directly to the development of severe PAH. Answering this question is the aim of the recent paper reviewed in today’s post by Jernigan et al., “Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension”. ROS in PH Many studies have shown that there is an imbalance of oxidant production and antioxidant capacity in the pulmonary vasculature of PH patients.… Read More...
08Aug/17

Inflammation in Pulmonary Hypertension – A Scientific Perspective, with a focus on Hypoxic PH

What is inflammation? Inflammation is a complex biological response of the body to remove foreign objects like pathogens (bacteria, virus, fungus), damaged cells, or irritants. It involves cells of the immune system, blood cells, tissue cells, and chemical mediators such as cytokines, chemokines, and reactive oxygen species. We typically have negative connotations associated with inflammation, which is justified, but not all cases of inflammation are negative. We need inflammatory processes to remove harmful pathogens, damaged cells or irritants. The problem arises when this inflammation goes unresolved, and becomes a chronic condition. There is another common harmful side of the immune system, however.… Read More...
12Jan/17

“Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension” – A Review of Lipid Peroxidation in PH

A key underpinning in the pathological development of PAH is thought to be the abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs), and it is well known that oxidative stress plays a key role in this process. One oxidative stress pathway is lipid peroxidation, which has been found to contribute to abnormal PASMC growth. A major end product of lipid peroxidation processes, specifically from omega-6 peroxidation, is the compound 4-hydroxynonenal (HNE). [For those of a chemistry bent, 4-HNE is an aldehyde]. Of interest is the fact that 4-HNE has been found to contribute to PASMC growth and this compound has also been found in excess in the pulmonary arteries of PH patients.… Read More...
20Oct/16

“Matrix metalloproteinases and their inhibitors in pulmonary hypertension” – A Review

This past week, I delved into the arena of Matrix Metalloproteinases and their role in disease and Pulmonary Hypertension. One of the first papers that I read with regards to this is by S.S. Pullamsetti et al. entitled “Matrix metalloproteinases and their inhibitors in pulmonary hypertension”. My review and summary of this paper is below. Abbreviations: ECs = Endothelial Cells SMCs = Smooth Muscle Cells ECM = Extracellular Matrix PAH = Pulmonary Arterial Hypertension MMPs = Matrix Metalloproteinases TIMPs = Tissue Inhibitors of Matrix Metalloproteinases In PAH, complex remodeling is observed in the pulmonary vasculature that involves all components of the blood vessel.… Read More...
06Sep/16

“Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung” – A Review

This is a review and summary of a recent paper entitled “Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung”. In this study, metabolomic profiling was used in an animal model of PH to try to identify biomarkers of early stage PH, in hopes of identifying a process to diagnose PH earlier. At the end of this post, I’ve included a chart summarizing all of the biomarkers found in the study. Some terms: MCT = Monocrotaline SMC = Smooth Muscle Cell EC = Endothelial Cell Summary & Key Findings In the MCT animal model, they observed metabolic changes in “multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis.” While less pronounced, the metabolic data derived from this study compared favorably with prior work carried out in humans with PH: “In support of our data in the MCT-exposed rat, PH patient metabolomic data also observed a significant elevation of glucose and fructose 6-phosphate levels [7].… Read More...
30Aug/16

“AMPK modulates Hippo pathway activity to regulate energy homeostasis” – A Review

I’m on a YAP kick lately! This is another paper about the Hippo pathway and YAP but in relation to glucose homeostasis and cellular energy stress. In summary, the Hippo pathway is a tumor suppressor pathway. Energy stress, defects in glucose metabolism, and glucose starvation, all activate this pathway and decrease oncogenic downstream components (specifically YAP). The implications? Metabolic regulation and glucose homeostasis are integral pieces in the puzzle that is “What causes cancer?” Summary & Key Points: The Hippo pathway is a signaling pathway that is involved in the control of tissue and organ size in the body. Loss of the Hippo path components leads to tumor formation, which suggests that the Hippo path is crucial for suppressing tumors.… Read More...
26Aug/16

“Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension” – A Review

This was a very interesting and exciting paper that I discovered today via Pulmonary Hypertension News: “Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension”. I’m a large proponent of the hypothesis that metabolic dysregulation and immune dysfunction are key drivers in the development of pulmonary hypertension. This paper adds weight to my case that the former is most likely a key element in PH pathogenesis. I’ve also always believed that due to the enigmatic nature of the disease, and presence of “cancer”, “autoimmune”, and “metabolic dysregulation” like features, solving PH can potentially solve problems like cancer and autoimmunity. A few examples from the paper as it pertains to cancer: “Here, the identification of glutaminolysis as a mechanoactivated process coregulated with aerobic glycolysis advances our understanding of the regulatory hierarchy seen in the metabolic reprogramming in PH.… Read More...
25Aug/16

“Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension” – A Synopsis

Below is a synopsis of this video “Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension”, a talk by Rubin Tuder given at the Vera Moulton Wall Center for Pulmonary Vascular Disease: Summary He has shown the first statistical correlation of perivascular inflammation with mPAP and vascular remodeling (~60 lungs from IPAH, hereditary PAH, scleroderma associated PH) despite current PH drugs: Schistosomiasis – 200 million people infected by parasite – in temperate areas like China, Brazil, Sudan, etc. 1-10% of people infected will develop PH Rather than talking about things where we don’t know what the cause/effect relationship is in PH (IPAH, Scleroderma, etc.), we should start with Schistosomiasis, which is something where we know what the culprit is: an egg nesting around vasculature that causes vasculopathy.… Read More...