ABSTRACT
While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice overexpress ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-ß protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD.
Subject(s)
Alzheimer Disease/genetics , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Hypertension/metabolism , Monocytes/enzymology , Peptidyl-Dipeptidase A/genetics , Animals , Disease Models, Animal , Humans , Hypertension/drug therapy , Hypertension/genetics , Peptidyl-Dipeptidase A/metabolismABSTRACT
Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several aspects of the immune response. ACE 10/10 mice overexpress ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization toward a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with melanoma, bacterial infection, or Alzheimer disease. As shown in ACE 10/10 mice, enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges.
Subject(s)
Granulocyte Precursor Cells/enzymology , Granulocyte Precursor Cells/immunology , Immunity, Cellular/genetics , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Animals , Mice , Mice, KnockoutABSTRACT
Angiotensin-converting enzyme (ACE) is best known for the catalytic conversion of angiotensin I to angiotensin II. However, the use of gene-targeting techniques has led to mouse models highlighting many other biochemical properties and actions of this enzyme. This review discusses recent studies examining the functional significance of ACE tissue-specific expression and the presence in ACE of two independent catalytic sites with distinct substrates and biological effects. It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation, and immunity.
Subject(s)
Peptidyl-Dipeptidase A/physiology , Animals , Cytokines/genetics , Cytokines/metabolism , Endothelial Cells/metabolism , Gene Expression , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/immunology , Humans , Hypertension/etiology , Immunity/physiology , Immunologic Memory , Kidney/metabolism , Kidney/physiology , Mice , Mice, Knockout , Peptides , Peptidyl-Dipeptidase A/chemistry , Phenotype , Protein Interaction Domains and MotifsABSTRACT
Hypertension is an epidemic health concern and a major risk factor for the development of cardiovascular disease. Although there are available treatment strategies for hypertension, numerous hypertensive patients do not have their clinical symptoms under control and it is imperative that new avenues to treat or prevent high blood pressure in these patients are developed. It is well established that increases in sympathetic nervous system (SNS) outflow and enhanced renin-angiotensin system (RAS) activity are common features of hypertension and various pathological conditions that predispose individuals to hypertension. More recently, hypertension has also become recognized as an immune condition and accumulating evidence suggests that interactions between the RAS, SNS and immune systems play a role in blood pressure regulation. This review summarizes what is known about the interconnections between the RAS, SNS and immune systems in the neural regulation of blood pressure. Based on the reviewed studies, a model for RAS/neuroimmune interactions during hypertension is proposed and the therapeutic potential of targeting RAS/neuroimmune interactions in hypertensive patients is discussed. Special emphasis is placed on the applicability of the proposed model to obesity-related hypertension.
