Abstract
The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca2+, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca2+-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dys-function during the progression of heart failure.
Highlights
Heart failure affects an estimated 40 million people worldwide and the prevalence of this global pandemic in the United States is expected to increase to about 8 million by 2030 from the current level of 6.4 million [1,2,3]
Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure
A great deal of progress has been made for the development of therapy for heart failure and various interventions including those for RAS blockade have been observed to improve heart function and delay the occurrence of heart failure but their beneficial effects in reducing mortality and morbidity are not satisfactory
Summary
Heart failure affects an estimated 40 million people worldwide and the prevalence of this global pandemic in the United States is expected to increase to about 8 million by 2030 from the current level of 6.4 million [1,2,3]. It should be mentioned that ANG II blockade has been shown to attenuate changes in collagen expression, β-adrenoceptor signal transduction system and ATP-induced increase in [Ca2+]i in the failing heart [123,124,125,126] These observations support the view that the activation of RAS and elevated plasma levels of ANG II play an important role in the pathogenesis of cardiac dysfunction and subcellular abnormalities in heart failure. Hemodynamic parameters LVEDP (mmHg) LVSP (mmHg) LV + dP/dt (mmHg/s) LV - dP/dt (mmHg/s)
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