Biomedical subjects

Ivan C Gerling

Publications and source records attributed to Ivan C Gerling.

21 records · Page 2Linked to original sources

PubMed2003

Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype.

Chronic inappropriate (relative to dietary Na+ intake) elevations in circulating aldosterone (ALDO), termed aldosteronism, are associated with remodeling of intramural arteries of the right and left heart. Lesions appear at week 4 of treatment with ALDO and 1% dietary NaCl in uninephrectomized rats (ALDOST) and include invading monocytes, macrophages and lymphocytes with intracellular evidence of oxidative and nitrosative stress, myofibroblasts, and perivascular fibrosis. In this study, we tested the hypothesis that an immunostimulatory state with activated circulating peripheral blood mononuclear cells (PBMCs) precedes this proinflammatory and profibrogenic cardiac phenotype and is initiated by reduction in the cytosolic free Mg2+ concentration ([Mg2+]i). At 1 and 4 wk of ALDOST (preclinical and clinical stages, respectively), we monitored serum Mg2+, PBMC [Mg2+]i and cytosolic free [Ca2+] (via fluorimetry), and expressed genes (via microchip array) as well as markers of oxidative and nitrosative stress in plasma [alpha1-antiproteinase activity (alpha1-AP)] and cardiac tissue (immunohistochemical detection of gp91phox subunit of NADPH oxidase and 3-nitrotyrosine). Age- and gender-matched unoperated and untreated (UO) rats and uninephrectomized salt-treated (UN) rats served as controls. Serum [Mg2+] was unchanged by ALDOST. In contrast with UO and UN, [Mg2+]i and plasma alpha1-AP were each reduced (P < 0.05) at weeks 1 and 4. The decline in PBMC [Mg2+]i was accompanied by Ca2+ loading. Differential (twofold and higher) expression (up- and downregulation) in PBMC transcriptomes was present at week 1 and progressed at week 4. Involved were genes for the alpha1-isoform of Na+-K+-ATPase, the ATP-dependent Ca2+ pump, antioxidant reserves, inducible nitric oxide synthase, and PBMC activation with autoimmune responses. Expression of 3-nitrotyrosine and activation of gp91phox were seen in inflammatory cells that invaded intramural arteries. Thus early in aldosteronism (preclinical stage), an immunostimulatory state featuring activated circulating PBMCs with reduced ionized [Mg2+]i and oxidative and nitrosative stress precedes and may even predispose to coronary vascular lesions that first appear at week 4.

Animals↗

PubMed2003

Aldosteronism in heart failure: a proinflammatory/fibrogenic cardiac phenotype. Search for biomarkers and potential drug targets.

Heart failure is a major health problem of epidemic proportions. Irrespective of its etiologic origins, a dysfunction of this normally efficient muscular pump is associated with systemic consequences, a progressive downhill clinical course and poor prognosis. Ventricular dysfunction is ultimately accompanied by neurohormonal system activation that accounts for: the congestive heart failure syndrome; an induction of oxi/nitrosative stress; adverse vascular remodeling; and activation of the immune system that contributes to a wasting syndrome known as cardiac cachexia. Circulating effector hormones of the renin-angiotensin-aldosterone system are an integral feature of this neurohormonal activation; they have systemic consequences. Insights into the pathophysiology of heart failure will identify improved methods of prevention, including biomarkers to aid in its detection and identification of risk, and to the development of specific drug targets. Herein we address one aspect of the neurohormonal profile of heart failure, namely that related to aldosteronism. Our focus is directed at the link between aldosteronism and its adverse influence on coronary vasculature structure, a proinflammatory/fibrogenic cardiac phenotype, which is based on an immunostimulatory state that includes activated peripheral blood mononuclear cells.

Aldosterone↗

PubMed2003

Toward a broader understanding of aldosterone in congestive heart failure.

Discovered some 50 years ago, aldosterone (ALDO) has come to be recognised as a mineralocorticoid hormone with well-known endocrine properties in epithelial cells that contribute to the pathophysiology of congestive heart failure. This includes Na+ resorption at the expense of K+ excretion in classic target tissues: kidneys, colon, sweat and salivary glands. Though less well known, Mg2+ excretion is likewise enhanced by ALDO, while adrenal ALDO secretion is regulated by extracellular Mg2+ ([Mg2+]o). An emerging body of information has and continues to identify other endocrine actions of ALDO receptor-ligand binding. They include: promoting an efflux of cytosolic free Mg2+, or [Mg2+]i, in exchange for Na+ in such non-epithelial cells as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions that involve regulation of cerebrospinal fluid composition produced by epithelial cells of the choroid plexus, activity of the hypothalamic paraventricular nucleus involved in Na+ appetite, Na+ and H2O excretion and sympathetic nerve activity, and the regulation of TNF-alpha production from central and/or peripheral sources. Extra-adrenal steroidogenesis and auto/paracrine properties of ALDO generated de novo in the cardiovasculature are now under investigation and preliminary findings suggest they contribute to tissue repair. The past decade has witnessed a revival of interest in this steroid molecule. In years to come, an even broader understanding of ALDOs contribution to the pathophysiology of congestive heart failure will undoubtedly emerge.

Aldosterone↗