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Review
. 2022 Oct 22;11(21):3336.
doi: 10.3390/cells11213336.

Angiotensin II-Induced Signal Transduction Mechanisms for Cardiac Hypertrophy

Sukhwinder K Bhullar  1 , Naranjan S Dhalla  1
Affiliations
Review

Angiotensin II-Induced Signal Transduction Mechanisms for Cardiac Hypertrophy

Sukhwinder K Bhullar et al. Cells. .

Abstract

Although acute exposure of the heart to angiotensin (Ang II) produces physiological cardiac hypertrophy and chronic exposure results in pathological hypertrophy, the signal transduction mechanisms for these effects are of complex nature. It is now evident that the hypertrophic response is mediated by the activation of Ang type 1 receptors (AT1R), whereas the activation of Ang type 2 receptors (AT2R) by Ang II and Mas receptors by Ang-(1-7) exerts antihypertrophic effects. Furthermore, AT1R-induced activation of phospholipase C for stimulating protein kinase C, influx of Ca2+ through sarcolemmal Ca2+- channels, release of Ca2+ from the sarcoplasmic reticulum, and activation of sarcolemmal NADPH oxidase 2 for altering cardiomyocytes redox status may be involved in physiological hypertrophy. On the other hand, reduction in the expression of AT2R and Mas receptors, the release of growth factors from fibroblasts for the occurrence of fibrosis, and the development of oxidative stress due to activation of mitochondria NADPH oxidase 4 as well as the depression of nuclear factor erythroid-2 activity for the occurrence of Ca2+-overload and activation of calcineurin may be involved in inducing pathological cardiac hypertrophy. These observations support the view that inhibition of AT1R or activation of AT2R and Mas receptors as well as depression of oxidative stress may prevent or reverse the Ang II-induced cardiac hypertrophy.

Keywords: AT1 receptors; AT2 receptors; Ang II-induced cardiac hypertrophy; Ang II-induced signal transduction; Ca2+-overload and calcineurin; mass receptors; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A schematic representation for the involvement of different angiotensin peptides such as Ang II and Ang (1-7) as well as their receptors for the development of cardiac hypertrophy upon the activation of renin-angiotensin system. It is pointed out that although other angiotensin peptides such as Ang III, Ang IV and Ang (1-9) are also formed during the activation of renin-angiotensin system, their role and receptor mechanisms are not fully understood.
Figure 2
Figure 2
A schematic representation for the AT1 receptors and phospholipase C mediated signal transduction pathways for the development of Angiotensin II- induced cardiac hypertrophy. The activation of AT1R has been shown to promote Ca2+—entry through sarcolemmal Ca2+ channels and increase the intercellular concentration Ca2+, which may also contribute to activating Ca2+ calmodulin kinase for the occurrence of cardiac hypertrophy.
Figure 3
Figure 3
A schematic representation for the AT1 receptors and redox status mediated signal transduction pathway as well as AT1 receptor and oxidative stress-calcineurin pathway for the development of acute and chronic cardiac hypertrophy, respectively. Although different other signal transduction pathways such as ROS, PKC, ERK1/2, Akt, NF-κB and NOX, p38 MAPK, c-JNK, NF-κB have been identified to explain Ang II—induced pathological (maladaptive) cardiac hypertrophy, their involvement including that of Ca2+, calmodulin in the development of physiological (adaptive) cardiac hypertrophy is poorly understood.
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