Review articleAdaptive and Maladaptive Remodeling of Cardiomyocyte Excitation-Contraction Coupling by Angiotensin II
Section snippets
Cardiac RAS
The RAS comprises a cascade of enzymatic reactions resulting in the formation of Ang II from the substrate angiotensinogen (Agt). In this classic concept, the process is initiated when the enzyme renin acts on liver-derived Agt, an α-globulin, to release the decapeptide angiotensin I (Ang I). This decapeptide has limited intrinsic pharmacologic activity and is cleaved by either angiotensin-converting enzyme (ACE) or chymases to yield the highly active octapeptide Ang II. Angiotensin II has
Acute Modulation of Cardiomyocyte ECC by Ang II
Modulation of cardiomyocyte ECC is one of the many cellular responses ascribed to Ang II in the heart (Kobayashi et al. 1978). The precise mechanisms underlying Ang II–induced inotropic action are still debated today, but they are clearly linked to direct or indirect changes in the activity of key ECC transporters, such as the sodium-hydrogen exchanger (NHE), NCX, SERCA2, RyRs, and the L-type Ca2+ channels. Acute in vitro studies have demonstrated that Ang II is capable of regulating myocyte
Maladaptive Modulation of Cardiomyocyte ECC by Ang II
In contrast to “normal heart” preparations and cardiomyocytes, it is consistently reported in both human and experimental settings that either the positive inotropic response to acute Ang II exposure is diminished or the negative inotropic effect is enhanced in various pathologic states (Moravec et al., 1990, Senzaki et al., 1998). These data suggest that cardiac remodeling in heart disease states may be associated with maladaptive changes in the inotropic responsiveness to Ang II of cardiac
Overexpressing or Knocking Out the RAS in the Mouse
A critical view on data produced during the past 15 years for a variety of genetically engineered mice carrying tissue-specific gain- or loss-of-function for RAS components demonstrates significant differences in potency of RAS elements to disrupt blood pressure control and/or cardiac integrity (partially reviewed in Bader, 2010, Reudelhuber et al., 2007). Unfortunately, for most of the mouse models produced to date, there is still a significant lack of information concerning the time course of
Adaptive and Maladaptive ECC Remodeling in TG1306/1R
Various studies performed on TG1306/1R mice consistently demonstrated that long-term overexpression of cardiac Agt—leading to enhanced Ang II biosynthesis—has a detrimental effect on ECC in the myocardium, even when there is no significant elevation of afterload. In vivo, the data demonstrated that myocardial remodeling was associated with systolic and diastolic dysfunction in ∼50-week-old TG1306/1R. These changes were preceded by a subtler sign of relaxation delay observed in hearts of
Significance and Limitations
Previous work has demonstrated that pharmacologic inhibition of the RAS reversed the hypertrophic remodeling at the organ level in TG1306/1R mice (Mazzolai et al. 2000). Beyond this mouse model, the benefit of RAS inhibition in heart failure has been demonstrated in several randomized clinical trials (see, eg, Lorell and Carabello 2000). Recent work has extended this concept by demonstrating that RAS blockade improves cardiac function and metabolism in patients with diabetes and/or
Acknowledgments
This work was supported by the Swiss National Science Foundation (31-111983), Schweizerische Herzstiftung, and Novartis Research Foundation to ME. AD was partially funded by a postdoctoral fellowship from the Swiss National Science Foundation.
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