angiotensinogen and Cardiac-Output--Low

Angiotensin II, the effector peptide of the renin-angiotensin system, regulates cellular growth in response to developmental, physiological, and pathological processes. The identification of renin-angiotensin system components and angiotensin II receptors in cardiac tissue suggests the existence of an autocrine/paracrine system that has effects independent of angiotensin II derived from the circulatory system. To be functional, a local renin-angiotensin system should produce sufficient amounts of the autocrine and/or paracrine factor to elicit biological responses, contain the final effector (angiotensin II receptor), and respond to humoral, neural, and/or mechanical stimuli. In this review, we discuss evidence for a functional cardiac renin-angiotensin system.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Cardiac Output, Low; Heart; Humans; Myocardium; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System

The cardiac vasculature and myocardium contain components of the renin-angiotensin system (RAS), which may regulate local growth and cellular function. Alterations in the expression or action of these components, which include angiotensin converting enzyme (ACE), angiotensinogen, and angiotensin II type-1 receptors, may contribute to the development of disease, such as hypertension, left ventricular hypertrophy, myocardial infarction, and end-stage heart failure. ACE is one RAS component found to have genetic variants associated with cardiovascular disease. Molecular variants in any of the RAS components may affect signalling pathways, possibly increasing the risk of heart failure. In addition, variants may exacerbate the deleterious effects of altered RAS expression on cardiac function. Genetic variation in RAS components may affect therapy with ACE inhibitors and receptor-blocking agents. Although at present there is no compelling reason to target molecular variations for treatment, a new era in selective pharmacological therapy for cardiovascular disease may be imminent.

Topics: Angiotensin II; Angiotensinogen; Bradykinin; Cardiac Output, Low; Cardiomegaly; Genetic Variation; Heart Diseases; Humans; Peptidyl-Dipeptidase A; Receptors, Angiotensin; Renin-Angiotensin System

Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II-mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (approximately 45% reduction in dP/dtmax and dP/dtmin at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.

Topics: Aging; Angiotensin II; Angiotensinogen; Animals; Calcium; Calcium-Transporting ATPases; Cardiac Output, Low; Cardiomegaly; Cardiomyopathy, Dilated; Male; Mice; Mice, Transgenic; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Myosin Heavy Chains; Phenotype; Promoter Regions, Genetic; Rats; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Remodeling