Role of Heme Oxygenase and its Metabolites in the Regulation of Blood Pressure
One of the tenants of renal physiology is that increases in renal perfusion pressure (blood pressure) result in increased excretion of sodium and water. This phenomenon is known as the renal pressure-natriuresis relationship. Interestingly, in all animal models of hypertension tested, the relationship between increases in renal perfusion pressure and sodium and water excretion is altered so that hypertensives require higher levels of renal perfusion pressure to excrete normal amounts of sodium and water as compared to individuals with normal blood pressure. My lab has been studying the relationship between several hormone systems and the regulation of renal pressure-natriuresis in hypertension. Currently, we are focused on the heme oxygenase system and its metabolites in modifying the renal pressure-natriuresis relationship in hypertension. Heme oxygenase (HO) is an enzyme responsible for the breakdown of heme into biliverdin, carbon monoxide (CO), and free iron. Biliverdin is then reduced to bilirubin by the enzyme biliverdin reductase as outline in the figure below.
Heme oxygenase enzymes are found in two major forms. HO-1 is the inducible isoform of HO. HO-1 can be induced by several physiological and pathophysiological stimuli including: hypoxia, ischemia, exposure to nephrotoxins, and in response to inflammation. HO-2 is the constitutive express isoform of HO that is expressed in low levels in most tubule and vascular structures of the kidney. My lab has been interested in the renal mechanisms that mediate the antihypertensive actions of HO-1 induction in the kidney. Our group first reported that kidney specific induction of HO-1 was able to reduce blood pressure in a model of angiotensin (Ang) II-dependent hypertension. We have also demonstrated transgenic mice in which the HO-1 isoform is over-expressed specifically in thick ascending loop of Henle (TALH) cells in the kidney exhibit a lower blood pressure after infusion of Ang II. Interestingly, these mice also have decreased levels of the Na, K, 2Cl (NKCC2) transporter in the TALH cells of the kidney. We are currently performing experiments to determine the regulation of the NKCC2 transporter by HO-1 and its metabolites. We have also developed conditional knockouts of HO-1 in specific nephron segments such as the proximal tubule, and collecting duct to determine the effects of decreased levels of HO-1 in these nephron segments on sodium reabsorption and blood pressure.
Our lab is also focused on the role of increased levels of plasma bilirubin in the prevention of cardiovascular disease. Many large scale patient population studies have demonstrated a link between increased levels of plasma bilirubin (between 50% to 2 fold increase) and the prevention of cardiovascular diseases including stroke, heart disease, and hypertension. However, despite these clinical correlations, the mechanism by which moderate increases in plasma bilirubin protect against cardiovascular disease is unknown. We have recently developed a mouse model of moderate hyperbilirubinemia which closely mimics the increase in plasma bilirubin observed in the human patient populations by targeting of hepatic UGT1A1 enzyme with antisense morpholino oligonucleotides. UGT1A1 is the enzyme in the liver responsible for the conjugation of bilirubin into the bile for elimination. By blocking the levels of this enzyme, we are able to increase the levels of unconjugated and total bilirubin in the plasma between 50% to 2 fold. We have found that moderate increases in plasma bilirubin in this range can lower blood pressure in a mouse model of Ang II dependent hypertension. The decrease in blood pressure with moderate hyperbilirubinemia is associated with increases in renal blood flow and glomerular filtration rate. We also found that moderate increases in plasma bilirubin result in decrease reactive oxygen species production in Ang II infused mice as well as a dramatic increase in the bioavailability of nitric oxide (NO). Ang II infusion is also associated with increased levels of endothelin production in the vasculature which are diminished by moderate hyperbilirubinemia. We are currently working to determine the roles of reactive oxygen species, NO, and endothelin to the antihypertensive actions of moderate hyperbilirubinemia. We are also interested in developing additional targets to specifically decrease bilirubin conjugation in the liver as potential anti-hypertensive therapies.
Role of Heme Oxygenase and its Metabolites in Metabolic Diseases
Our lab is also interested in role of the HO system in obesity. We were the first to demonstrate that chronic induction of HO-1 lowers body weight by increasing oxygen consumption and carbon dioxide (CO2) production, two indicators of increased metabolism, increased heat production, another indicator of increased metabolism and increasing physical activity all without changing food intake. We are currently developing novel mouse models which lack HO-1 in adipocytes, liver, and in the brain to determine the role of the HO system in the regulation of body weight and metabolism.
Carbon monoxide is a metabolite produced in the body via the actions of heme oxygenase. We have utilized drugs that release carbon monoxide so called Carbon Monoxide Releasing Molecules (CORMs) to investigate the role of carbon monoxide as a potential anti-obesity drug. We have shown that chronic treatment with CORMs is able to prevent the development of obesity as well as REVERSE obesity in mice fed a diet of "junk food ". CO prevents and reverses obesity by increasing metabolism without affecting food intake. CO treatment also has a profound effect on the biology of the white fat cells making them look more like a brown fat cells. Brown fat cells are very good at burning fat instead of storing it. CO is also able to decrease the production of inflammatory markers from the fat to reduced inflammation which is a serious complication of obesity. We are currently investigating the mechanism by which CO can increase metabolism and change the phenotype of white adipose tissue. We are currently focusing on the second messenger systems activated by CO as well as its effect on mitochondria which are the powerhouses of the cell.
Bilirubin is another metabolite of heme oxygenase which has been shown to play an important role in the development of metabolic diseases. Several human population studies have reported an inverse correlation between serum bilirubin levels and the development of type II diabetes and obesity. Increased plasma bilirubin levels have also been reported to protect against non-alcoholic fatty liver disease (NAFLD) which is the leading cause of liver disease in obese patients. There are currently no FDA approved therapeutics for the treatment of NAFLD. We have recently discovered that bilirubin can act as a nuclear hormone receptor to alter fatty acid metabolism in the liver to increase glucose sensitivity and decrease fatty liver disease. We are currently examining these novel pathways to determine their role in the protective actions that increased levels of bilirubin has on type II diabetes and obesity. Biliverdin reductase is the enzyme responsible for the reduction of biliverdin, produced by HO, to bilirubin. We have created a novel model of BVRA knockout in the liver and fat to determine the role of intracellular bilirubin generation on the protection from type II diabetes and obesity. This model will allow us to determine the signaling pathways that are activated by intracellular bilirubin as well as by the BVRA enzyme itself.
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