PKC in heart failure

Question 1

Role of Gq in heart failure

Answer 1

D'angelo 1997
Adams et al 1997
Akther et al 1997 
Problem with transgenic mice
Fan et al 2005

Question 2

Role of PLC in heart failure

Answer 2

Arthur et al 2001
Fitz et al 2009
Dent et al 2004
Woodcock et al 2015 and 2016

Question 3

Role of PKC in heart failure

Answer 3

In vivo experiments and tissue culture express a variety of results using phorbol esters as PKC agonists

Dom et al 2002- PKC it mediates contractility and hypertrophy in cultured cells

PKC is activated by IP3 and DAG

Question 4

What is the problem with using PKC in tissue culture and extracts

Answer 4

The PKC family is huge. It has about 120 different isoforms, and within these, there is also a lot of multiplicity and crossover of the family during various pathological and physiological states

Question 5

What is the problem with using PKC in the heart

Answer 5

PKC expression in the heart has also been demonstrated to be highly variable. This could depend on either the cell type, the species and the developmental stage. And so for example in 1994, Steinberg et al outlined that the expression of different PKC isoforms was different if you examined neonatal hearts, compared to adult hearts. There were also differences based on the genetics of the rat and mice, and we can consider even rabbits. The main implication of this is that the results from various studies explaining the results of in vivo experiments must also be read with caution

Question 6

What is the problem with using PKC expression in the heart studies

Answer 6

Although the general consensus is that in the adult human heart, the commonest are a b d e ë. However, as mentioned before there is extremely high multiplicity of these heart cells in various tissues.

In addition, the activity of each PKC isoform is dependent on

1. How much is expressed
2. Its localisation within the heart
3. Its level of phosphorylation

Question 7

Why does the fact that PKC expression in the heart based on

1. How much is expressed
2. Its localisation within the heart
3. Its level of phosphorylation

Matter in disease

Answer 7

This matters because in diseases states, such as heart failure, these findings are influenced and can be highly variable. The findings from volume overloaded, TAC or ischaemic model of heart failure might be different.

Question 8

PKC knockout

Answer 8

Braz et al in 2004 created PKCa knockout mice and subjected them to TAC and what they found out was that these mice were protected from insult and there was about a 50% reduction in the chamber dilation. Conversely, overexpression of PKC caused contractile dysfunction before the heart remodelling took place at 4 months. By 8 months, however, the remodelling of the heart had occurred and there was both contractile dysfunction and hypertrophy.

Question 9

Have knockout studies been any better?

Answer 9

Unfortunately, knockout studies have not proven to be better unlike their utility in normal studies. This is because in the absence of a basic cardiac phenotype, and the fact that PKC is absent in various tissue of the body, the knockout of one could just lead to the up-regulation of another by opportunistic compensation. So the findings from Braz et al could just be due to upregulation of the other phenotypes. Irrespective of compensation, there was

Question 10

However, this effect could be negligible, and the next part of this essay will explain why

Answer 10

Hambleton et al 2006 observed that the dominant cardiac isoform was the PKC alpha form, with a little B expression although this was to a lower effect. Wakasaki et al in 1997 suggested that PKCb had a role in hypertrophy using transgenic knockout mice, however, Romano et al in 2001 and Li et al 2001 have described the opposite. The effect of compensation or a difference in species and laboratory methods could explain the difference

Question 11

PKC Therapeutics

Answer 11

Use of RUBOXOSTATRIN

Question 12

What is ruboxostatrin?

Answer 12

It was first introduced by Joy et al 2005 and it was used safely in human trials to reduce the effects of sugar in diabetes in the reduction of retinopathy by reducing the neo-vascularisation. It was reported to be PKCB selective

Question 13

What 2 studies rebutted the PKC B isoform role in hypertrophy in transgenic mice posed by Wakasaki et al in 1997

Answer 13

Romano et al in 2001 and Li et al 2001 have described the opposite. The effect of compensation or a difference in species and laboratory methods could explain the difference

Question 14

When was ruboxostatrin used in the heart

Answer 14

However, In 2010 Li, Chen et al described that RUBOXOSTATRIN was in fact also alpha selective. In a large study of 100 mice treated with ruboxostatrin compared to mice treated with conventional B blockers, after subjection to TAC for 4 weeks, a high number the mice died initially, but of the mice that survived, they were either treated with a B blocker or ruboxostatrin. What was even more interesting is that the mice treated with high dose ruboxostatrin showed no lethalithy whatsoever, suggesting a protective role in cardiac pressure overload. To further confirm that this effect was PKCa mediated and not PKCb/gamma, they did a second study and knocked out PKCb. After TAC for 4 weeks, these mice still had the protective effect of ruboxostatrin strongly suggesting PKCa

Question 15

What is the final ruboxostatrin study apart from Li Chen et al 2010

Answer 15

Ladage et al 2011 also showed a similar protective effect by ruboxostatrin on pig hearts, following MI induced HF.