The Anrep effect: 100 years later.

Area of Science:

• Cardiology
• Physiology
• Molecular Biology

Background:

• Myocardial stretch initiates rapid force increase via myofilament calcium sensitivity (Frank-Starling mechanism).
• A secondary, slower force increase occurs over 10-15 minutes, known as the Anrep effect, due to elevated calcium transient amplitude.
• The Anrep effect is the in vitro correlate of a phenomenon observed in the intact heart 100 years ago.

Purpose of the Study:

• To review and discuss the autocrine/paracrine mechanisms underlying the Anrep effect.
• To detail the signaling cascade initiated by myocardial stretch leading to the Anrep effect.
• To present evidence for the role of Na(+)/H(+) exchanger 1 (NHE1) and its blunting by RNA interference.

Main Methods:

• Review of experimental evidence supporting the signaling pathway of the Anrep effect.
• Investigation of myocardial stretch-induced signaling: angiotensin II, endothelin, mineralocorticoid receptor, EGF receptor transactivation, mitochondrial ROS, redox-sensitive kinases.
• Experimental validation using small hairpin interference RNA to silence NHE1 expression in the ventricular wall.

Main Results:

• Myocardial stretch activates a signaling cascade involving angiotensin II, endothelin, mineralocorticoid receptor, and EGFR transactivation.
• This cascade leads to increased mitochondrial reactive oxygen species (ROS) and activation of redox-sensitive kinases upstream of NHE1.
• NHE1 activation increases intracellular Na(+) concentration, subsequently enhancing Ca(2+) transient amplitude via the Na(+)/Ca(2+) exchanger, thus causing the Anrep effect.

Conclusions:

• The Anrep effect is a complex response to myocardial stretch mediated by a specific signaling pathway.
• The Na(+)/H(+) exchanger 1 (NHE1) plays a crucial role in the Anrep effect by modulating intracellular sodium and calcium levels.
• Silencing NHE1 expression effectively blunts the Anrep effect, highlighting its therapeutic potential.