Heart Programming During Development: LHS ≠ RHS
Wnt is important for various processes during heart development - for instance second heart field (SHF) progenitor proliferation and differentiation (bear with me and hold on to this term for a while), atrioventricular junction development, ion channel gene expression, etc.
Heart Programming During Development: LHS ≠ RHS
Knowing your heart
Let's brush up our textbook knowledge about the heart. What do we know?
The heart is a fist-sized organ located in our rib cage which is responsible for pumping blood to the entire body. It is divided into the left and the right sides, by a septum, which is further subdivided into the top atrium (or auricle) and the lower ventricle. It has two types of blood vessels the arteries that carry blood away from the heart and the veins which carry the blood to the heart. It is majorly comprised of cardiomyocytes - branched striated muscle cells that contract and relax in order to pump the blood.
OK, pause! let's rewind a bit and focus on the fact that the heart has a left and a right side. These two differ only in the direction and type of blood they pump. Since the basic function remains the same, both sides are morphologically similar apart from the fact that the left ventricle has a thicker wall since it needs stronger contractions to pump blood all around the body. If the LHS is equal to RHS, hitherto, then why do clinical reports suggest a bias of arrhythmias towards the right ventricle (RV) over the left ventricle (LV)? Wait! What are arrhythmias?
Arrhythmias
When you break the word, you get 'a + rhythmia' i.e. abnormal rhythm or rate of heartbeat. It could either be slower (bradycardia), higher (tachycardia), or irregular (atrial fibrillation) than usual (60-100 beats per minute).
So back to our million-dollar question – if all’s the same in the left and the right side why do arrhythmias preferentially affect the right ventricle? What is telling them the difference between the left and the right?
And the answer is Wnt signaling!!!
Wnt knows right and wrong left
Wnt is important for various processes during heart development - for instance second heart field (SHF) progenitor proliferation and differentiation (bear with me and hold on to this term for a while), atrioventricular junction development, ion channel gene expression, etc. Time to get back to SHF. These are progenitor cells which eventually give rise to the RV and the right ventricular outflow tract. This gave the authors (Gang Li and his group at Washington) the lead to look at the differential expression of Wnt associated gene expression in the left versus the right ventricle.
In the current study, they employed a fine-tuned Wnt-LOF (loss of function) mice achieved by utilizing an allele of β-catenin (which was transcriptionally inactive but retained its cell adhesion properties) to lay hands on differentially expressed genes via RNAseq. To their excitement, they observed differential regulation of various genes in a chamber specific manner. Of all the dysregulated genes, 690 were specific to RV, 715 were exclusive to LV while 83 were shared by both. This drove the authors to peep and discovered various electrophysiological aberrations in these mice. Firstly, they observed an increase in excitability in the cardiomyocytes of the RV. Secondly, the conduction velocity of these cardiomyocytes was found to be significantly slower suggesting that Wnt plays a more crucial and vital role in the electrical conductance in the RV with respect to the LV. Further studies proved Connexin 43 (Cx43) guilty for it. Cx43 is a component of the gap junction encoded by the GJA1 (Gap junction alpha -1 protein) gene which facilitates intercellular communication and thereby has major implications in cardiomyocyte contraction.
Heightened excitability and a consequently reduced conductance predisposed these mice to ventricular tachycardia.
Hey(2), Wnt!
The cherry on the top was pinpointing the direct target of Wnt in the RV. Its partner in crime here was HEY2, an abbreviation for Hairy/enhancer-of-split related with YRPW motif protein 2. Ummm, let's just stick to HEY2!!! It is a helix-loop-helix containing transcriptional repressor which preferentially binds to the E-box sequence to bring about the repression.
So, all it all, Wnt activity in RV sets it different from the LV and its dysregulation here can genetically predispose an individual to RV-associated arrhythmias.
Take home message and cruncher
➢ The left and the right ventricles are from being similar to each other, but why would nature select for such a difference in the first place?