ABSTRACT
Aldosterone produced in adrenal glands by angiotensin II (Ang II) is known to elicit myocardial fibrosis and hypertrophy. This study was designed to test the hypothesis that Ang II causes cardiac morphological changes through the steroidogenic acute regulatory protein (StAR)/aldosterone synthase (AS)-dependent aldosterone synthesis primarily initiated in the heart. Sprague-Dawley rats were randomized to following groups: Ang II infusion for a 4-week period, treatment with telmisartan, spironolactone or adrenalectomy during Ang II infusion. Sham-operated rats served as control. Relative to Sham rats, Ang II infusion significantly increased the protein levels of AT1 receptor, StAR, AS and their tissue expression in the adrenal glands and heart. In coincidence with reduced aldosterone level in the heart, telmisartan, an AT1 receptor blocker, significantly down-regulated the protein level and expression of StAR and AS. Ang II induced changes in the expression of AT1/StAR/AS were not altered by an aldosterone receptor antagonist spironolactone. Furthermore, Ang II augmented migration of macrophages, protein level of TGFß1, phosphorylation of Smad2/3 and proliferation of myofibroblasts, accompanied by enhanced perivascular/interstitial collagen deposition and cardiomyocyte hypertrophy, which all were significantly abrogated by telmisartan or spironolactone. However, adrenalectomy did not fully suppress Ang II-induced cell migration/proliferation and fibrosis/hypertrophy, indicating a role of aldosterone synthesized within the heart in pathogenesis of Ang II induced injury. These results indicate that myocardial fibrosis and hypertrophy stimulated by Ang II is associated with tissue-specific activation of aldosterone synthesis, primarily mediated by AT1/StAR/AS signaling pathways.
Subject(s)
Angiotensin II/metabolism , Cardiomegaly/etiology , Cardiomegaly/metabolism , Cardiomyopathies/etiology , Cardiomyopathies/metabolism , Cytochrome P-450 CYP11B2/metabolism , Phosphoproteins/genetics , Adrenal Glands/metabolism , Animals , Biomarkers , Biopsy , Cardiomegaly/pathology , Cardiomyopathies/pathology , Collagen/metabolism , Disease Models, Animal , Disease Susceptibility , Fibrosis , Immunohistochemistry , Macrophages/immunology , Macrophages/metabolism , Male , Models, Biological , Myocardium/metabolism , Myocardium/pathology , Myofibroblasts/metabolism , Rats , Receptor, Angiotensin, Type 1/metabolism , Signal Transduction , Smad2 Protein/metabolism , Smad3 Protein/metabolismABSTRACT
The Center for Health Discovery and Wellbeing (CHDWB) is an academic program designed to evaluate the efficacy of clinical self-knowledge and health partner counseling for development and maintenance of healthy behaviors. This paper reports on the change in health profiles for over 90 traits, measured in 382 participants over three visits in the 12 months following enrolment. Significant changes in the desired direction of improved health are observed for many traits related to cardiovascular health, including BMI, blood pressure, cholesterol, and arterial stiffness, as well as for summary measures of physical and mental health. The changes are most notable for individuals in the upper quartile of baseline risk, many of whom showed a positive correlated response across clinical categories. By contrast, individuals who start with more healthy profiles do not generally show significant improvements and only a modest impact of targeting specific health attributes was observed. Overall, the CHDWB model shows promise as an effective intervention particularly for individuals at high risk for cardiovascular disease.
