Gq in heart failure Flashcards
What did D’angelo et al 1997 find
They used transgenic mice by using Gq over-expression with an alpha-myosin heavy chain promoter. They expressed gq about 2, 3 and 4 times, and what they demonstrated was that when Gq was expressed by 4 times, there was an increase in cardiac mass and heart size, a breakdown of the Starling curve (DRAW THE FRIKKIN CURVE), and individual myocytes were enlarged. The levels of ANP were also increased. These findings were only seen when Gq was expressed by 4 times, not 1, 2 or 3. What these could mean is that initially due to increased Gq, the heart can compensate, however, after a point there is an inability to compensate and this could account for the progression from compensated dysfunction to overt failure of the heart
Adams et al 1997
As D’angelo et al described the pathway leading to decompensation, Adams et al in 1997 wanted to see the process by which this decompensation lead to the development of heart failure.
Adenovirus infection
By adenovirus infection of cultured myocytes, they described that by the addition of a constitutively active Gq without its GTPase to attenuate and regulate it, what was happening was that after 8 hours, was that these cells began to shrink, and show signs of apoptosis, including a pyknosis and a karyolysis.
Pregnant infection
They then replicated this in pregnant mice. These mice were adenovirus infected, whilst pregnant, and
WT -/+ infection
Their study showed that in the WT-/+ cells when the gq activity was increased by 4 times, there was hypertrophy, confirming the findings of D’angelo et al in 1997 but about 8 times, these hearts began to show a dilated cardiomyopathy, as well as apoptosis. The interesting finding from this study was that the pregnant mice were protected from this effect of Gq, and only when the babies of these mice were born did they start to show effects. This suggests that the compensatory hypertrophy and then the development of HF occur in the same spectrum
Akther et al 1998
As the studies demonstrate that an increase in Gq leads to hypertrophy and heart failure signs, they wanted to see what Gq was inhibited. They induced TAC in mice for 4 weeks and then used cyclosporine (Gq inhibitor) to demonstrate what would happen. The addition of cyclosporine caused a reduction in hypertrophy from about 36% to half of it about 14%. (30% to 15%) In addition, there was a reduction in ANP by 7 times
Problem with transgenic
Now, these studies show a potential benefit of using transgenic mice in understanding the role of Gq-mediated pathways in the development of HF. Now the problem with these studies, however, is that standard transgenic and knockout studies impose a genetic alteration during embryonic and post natal phases that can drastically affect the phenotype of the animals. This is a potential weakness because the majority of HF in adults occur in the adult phase, in fact the over 65 population have amongst the highest rates of HF, as a result of cardiac injury in adulthood. This can lead to what is called a ‘developmental compensatory issue’
Fan et al 2005
To compensate for this, they used an inducible mouse model of HF. This system allowed them to look at what would happen in the adult mice if they induced Gq overexpression in the adult phase. Using injectable tamoxifen to switch on Gq after the completion of normal development and growth. They found that activation of Gq in adult mice caused a dilated cardiomyopathy, without even going to the hypertrophy stage as outlined by the previous studies. It also showed that this had early effects on calcium homoeostasis and contractility. At least two aspects of Ca2+ handling were markedly affected: the entry of Ca2+ into myocytes through the L-type Ca2+ channel is attenuated, and SERCA-2 activity is inhibited as a consequence of PLB dephosphorylation.
Jiang et al 2006
They used the same inducible Gq mouse model, however, they switched off the inducible Gq with tamoxifen, which lead to the reversal of HF characteristics
