Review article
Adaptive and Maladaptive Remodeling of Cardiomyocyte Excitation-Contraction Coupling by Angiotensin II

https://doi.org/10.1016/j.tcm.2010.06.001Get rights and content

Chronic elevation of plasma angiotensin II (Ang II) is a major determinant in the pathogenesis of cardiac hypertrophy and congestive heart failure. However, the molecular mechanisms by which the direct actions of Ang II on cardiomyocytes contribute to excitation-contraction coupling (ECC) remodeling are not precisely known. We review this question, as well as acute Ang II–mediated modulation of ECC. In addition, we discuss adaptive/maladaptive modulation of cardiomyocyte ECC under chronic endogenous Ang II overproduction in the heart induced by local overexpression of the of the renin-angiotensin system in the mouse.

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.

References (50)

  • BridgeJ.H.B. et al.

    What are the consequences of phosphorylation and hyperphosphorylation of ryanodine receptors in normal and failing heart?

    Circ Res

    (2008)
  • BersD.M.

    Cardiac excitation-contraction coupling

    Nature

    (2002)
  • CingolaniH.E. et al.

    Early signals after stretch leading to cardiac hypertrophy. Key role of NHE-1

    Front Biosci

    (2008)
  • De MelloW.C.

    Intracellular angiotensin II regulates the inward calcium current in cardiac myocytes

    Hypertension

    (1998)
  • De MelloW.C. et al.

    Angiotensin II and the heart. On the intracrine renin-angiotensin system

    Hypertension

    (2000)
  • DomenighettiA.A. et al.

    Angiotensin II–mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure

    Hypertension

    (2005)
  • GarciarenaC.D. et al.

    Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action

    J Appl Physiol

    (2008)
  • GomezA.M. et al.

    Increased exchange current but normal Ca2+ transport via Na+-Ca2+ exchange during cardiac hypertrophy after myocardial infarction

    Circ Res

    (2002)
  • GomezA.M. et al.

    Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure

    Science

    (1997)
  • GuoX. et al.

    Partial prevention of changes in SR gene expression in congestive heart failure due to myocardial infarction by enalapril or losartan

    Mol Cell Biochem

    (2003)
  • GusevK. et al.

    Angiotensin II–mediated adaptive and maladaptive remodeling of cardiomyocyte excitation-contraction coupling

    Circ Res

    (2009)
  • HarrapS.B. et al.

    Plasma angiotensin II, predisposition to hypertension, and left ventricular size in healthy young adults

    Circulation

    (1996)
  • HashidaH. et al.

    Serial changes in sarcoplasmic reticulum gene expression in volume-overloaded cardiac hypertrophy in the rat: effect of an angiotensin II receptor antagonist

    Clin Sci

    (1999)
  • IchiyanagiO. et al.

    Angiotensin II increases L-type Ca2+ current in gramicidin D-perforated adult rabbit ventricular myocytes: comparison with conventional patch-clamp method

    Pflugers Arch

    (2002)
  • IkenouchiH. et al.

    Effects of angiotensin-II on intracellular Ca2+ and Ph in isolated beating rabbit hearts and myocytes loaded with the indicator indo-1

    J Physiol

    (1994)
  • Cited by (8)

    • IL-22 ameliorated cardiomyocyte apoptosis in cardiac ischemia/reperfusion injury by blocking mitochondrial membrane potential decrease, inhibiting ROS and cytochrome C

      2021, Biochimica et Biophysica Acta - Molecular Basis of Disease
      Citation Excerpt :

      The RAS comprises a cascade of response resulting in the production of Angiotensin II (ANG II). Under cardiac injury, increased circulating ANG II binding with its receptor leads to hypertrophy and apoptosis of cardiomyocytes following cardiac injury [11–14]. However, whether IL-22 can protect cardiomyocyte apoptosis inducing by ANG II following cardiac injury remains unclear.

    • Swimming training promotes cardiac remodeling and alters the expression of mRNA and protein levels involved in calcium handling in hypertensive rats

      2014, Life Sciences
      Citation Excerpt :

      This peptide is the main effector molecule of the RAS, responsible for increased blood pressure by being a potent vasoconstrictor; moreover, Ang II also exerts proliferative, pro-inflammatory, pro-fibrotic activities, and stimulates the production of aldosterone in the adrenal glands (Briet and Schiffrin, 2010; Benigni et al., 2010), which acts on the distal tubules and collecting ducts of the nephron causing sodium retention, potassium secretion, water retention, and blood pressure increase. It is also known that chronic elevation of plasma Ang II is a major determinant in the pathogenesis of cardiac hypertrophy (Egger and Domenighetti, 2010). The B-type natriuretic peptide (BNP) is a peptide hormone derived from atrial and ventricular cardiomyocytes (Nakatsu et al., 2007).

    • Pathophysiology of heart failure

      2013, Essential Cardiology: Principles and Practice
    View all citing articles on Scopus
    View full text