Endothelin-1-induced Cardiomyocyte Hypertrophy

Cardiac hypertrophy describes an abnormal condition where the heart becomes enlarged. Under stresses such as high blood pressure, or reduced blood flow through the coronary arteries, the heart must work harder. Instead of dividing and increasing in number, individual cells grow larger and genes normally expressed in the embryonic ventricle are reexpressed. Initially this compensation is effective, but excessive hypertrophy can kill more cells, which increases the stress on the heart, causing surviving cells to grow even larger, which in turn leads to an ever accelerating cycle that can eventually result in heart failure. Cardiac hypertrophy can also cause diseases such as myocardial infarction and arrhythmia, and therefore it is important to try and better understand the molecular mechanisms underlying the development of this condition.

Several factors, such as increased mechanical loading and neuro-hormonal chemicals can induce hypertrophy. Endothelin-1 (ET-1) is a 21-amino acid vasoconstricter peptide which is able to induce cardiac hypertrophy. The binding of ET-1 to its cell surface G-protein coupled receptor triggers a signal transduction cascade (see Figure 1 below), which begins with the activation of phospholipase C (PLC), which hydrolyses phosphatidylinositol (PIP₂) to produce inositol triphosphate (IP₃) and diacylglycerol (DAG). IP₃ activates Ca²⁺ channels in the endoplasmic reticulum (ER) triggering the release of Ca²⁺ from intracellular stores. This Ca²⁺ and DAG then activate protein kinase C (PKC), which in turn phosphorylates L-type Ca²⁺ channels in the plasma membrane, activates them, and increases the flow of Ca²⁺ ions (I_Ca) into the cytosol. These ions then bind to calmodulin effectors (CaM) forming a Ca²⁺/calmodulin complex, which then in turn binds to and activates Ca²⁺/calmodulin-dependent phosphatase calcineurin (Cn) or Ca²⁺/calmodulin-dependent kinase II (CaMKII). These activate transcription factors such as the nuclear factor of activated T cells (NF-AT3) and AP-1. PKC also activates AP-1. NF-AT3 may activate expression of the beta-type myosin heavy chain gene (beta-MHC) with either AP-1 or GATA4.

The description of this signal transduction pathway was based on a paper by Weidong et al. (2000), which investigates the roles of CaMKII and calcineurin in ET-1-induced cardiomyocyte hypertrophy. The complete original paper reference is cited below:

Ca²⁺/Calmodulin-dependent Kinase II and Calcineurin Play Critical Roles in Endothelin-1-induced Cardiomyocyte Hypertrophy, Weidong Zhu, Yunzeng Zou, Ichiro Shiojima, Sumiyo Kudoh, Ruichi Aikawa, Dobun Hayashi, Miho Mizukami, Haruhiro Toko, Futoshi Shibasaki, Yoshio Yazaki, Ryozo Nagai, and Issei Komuro, 2000, The Journal of Biological Chemistry, 275, 15239-15245. (Full text and PDF versions of the article are available to subscribers on The Journal of Biological Chemistry website.)