8-epi-prostaglandin-f2alpha and Cardiomegaly

The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca(2+), coupled to oxidative stress with increased H(2)O(2) production and 8-isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal.

Topics: Animals; Cachexia; Calcium; Cardiomegaly; Dinoprost; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Hydrogen Peroxide; Hyperaldosteronism; Male; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Muscle, Skeletal; Muscular Atrophy; Myocardium; Myocytes, Cardiac; Necrosis; Rats; Rats, Sprague-Dawley; Recovery of Function; Time Factors; Ventricular Remodeling

Oxidative stress-mediated activation of protein kinase C (PKC) beta(2) in the myocardium has been implicated in the development of cardiomyopathy. Overexpression of PKCbeta(2) is associated with increased expression of connective tissue growth factor (CTGF) in myocardium, resulting in myocardial hypertrophy. We hypothesized that chronic treatment with the antioxidant N-acetylcysteine (NAC) would normalize oxidative stress-mediated overexpression of myocardial PKCbeta(2) and CTGF and attenuate the development of myocardial hypertrophy.. Control and streptozotocin-induced diabetic rats were treated with NAC in drinking water for 8 weeks. At termination rats were surgically prepared for hemodynamic measurement, subsequent to which their hearts were removed to evaluate cardiac performance and histological and biochemical changes. Further, the role of PKCbeta(2) in hyperglycemia-induced cardiomyocyte hypertrophy was tested in cultured neonatal cardiomyocytes.. Myocardial hypertrophy, characterized by an increased ratio of ventricle weight to body weight and cardiomyocyte cross-sectional area was found to be higher in untreated diabetic rats. Further, in myocardium, increased levels of 15-F(2t)-isoprostane were accompanied by an increased expression of membrane-bound PKCbeta(2) and CTGF. N-acetylcysteine treatment not only attenuated these changes but also prevented hyperglycemia-induced hypertrophy in cultured neonatal rat cardiomyocytes.. The results suggest that PKCbeta(2) overexpression represents a mechanism causing hyperglycemia-mediated myocardial hypertrophy, which can be prevented by the antioxidant N-acetylcysteine.

Topics: Acetylcysteine; Animals; Antioxidants; Cardiomegaly; Cell Size; Cells, Cultured; Collagen Type I; Collagen Type II; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental; Dinoprost; Glucose; Immediate-Early Proteins; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Male; Myocardium; Myocytes, Cardiac; Oxidative Stress; Protein Kinase C; Protein Kinase C beta; Rats; Rats, Wistar; Superoxides

Angiotensin II (Ang II)-induced renal damage is associated with perivascular inflammation and increased oxidative stress. We tested the hypothesis whether entacapone, a catechol-O-methyltransferase (COMT) inhibitor exerting antioxidative and anti-inflammatory properties, protects against the Ang II-induced inflammatory response and end-organ damage.. Samples from double-transgenic rats harbouring human renin and human angiotensinogen genes (dTGR) and normotensive Sprague-Dawley rats (SD) were assessed by light microscopy, immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and high pressure liquid chromatography. The effects of entacapone treatment for 3 weeks were examined in dTGR and SD.. Entacapone completely prevented cardiovascular mortality and decreased albuminuria by 85% in dTGR. Entacapone ameliorated Ang II-induced vascular and glomerular damage, leucocyte infiltration, and intercellular adhesion molecule-1 (ICAM-1) overexpression in the kidneys. Serum 8-isoprostane concentration, as well as renal nitrotyrosine and 8-hydroxydeoxyguanosine expressions, all markers of oxidative stress, were markedly increased in dTGR and normalized by entacapone. Entacapone also decreased p22phox mRNA expression in the kidney. COMT expression was increased by 500% locally in the renal vascular wall in dTGR; however, COMT activity in the whole kidney remained unchanged. Urinary dopamine excretion, a marker of renal dopaminergic tone, was decreased by 50% in untreated dTGR. Even though entacapone decreased renal COMT activity by 40%, the renal dopaminergic tone remained unchanged in entacapone-treated dTGR.. Our findings suggest that entacapone provides protection against Ang II-induced renal damage through antioxidative and anti-inflammatory mechanisms, rather than by COMT inhibition-induced changes in renal dopaminergic tone.

Topics: Angiotensin II; Animals; Animals, Genetically Modified; Biomarkers; Blood Pressure; Cardiomegaly; Catechol O-Methyltransferase; Catechols; Creatinine; Dinoprost; Disease Models, Animal; Dopamine; Enzyme Inhibitors; Hypertension; Inflammation; Intercellular Adhesion Molecule-1; Kidney; Kidney Diseases; Leukocytes; Male; Models, Cardiovascular; Nitriles; Norepinephrine; Rats; Rats, Sprague-Dawley; RNA, Messenger