In this study, we sought to define the effects of active vitamin D therapy in established cardiac hypertrophy and progression to heart failure using the DSS rat model fed a HS diet. We found that only PC had a significant effect on preventing further progression of pre-existing cardiac hypertrophy in DSS animals. In comparison, both PC and EP therapies attenuated the development of clinical and biochemical evidence of heart failure; there was an additive effect on the progression of heart failure in combination therapy with PC and EP. In fact, our gene array data demonstrates that attenuation of heart failure by combination therapy with PC and EP were associated with both common and unique gene expression profiles in heart. Thus, the potential RAS-independent mechanism by PC suggests additive effect of vitamin D therapy that could be explored in the treatment of heart failure. We also found that cardiac structural and functional improvements were coupled to inhibition of PKCα activation. These data are the first to demonstrate the prevention of progression of established cardiac hypertrophy and development of heart failure by an activated vitamin D compound in an animal model. These findings, combined with our previous findings that vitamin D therapy prevents the progression of cardiac hypertrophy8,28
suggests this therapy may be beneficial for those at risk to develop LVH, and those with pre-existing LVH, particularly if they are known to be vitamin D deficient (e.g. chronic renal failure patients).
A number of experimental studies demonstrate that vitamin D signalling is involved in cardiac hypertrophy. Endothelin-induced cardiomyocyte hypertrophy is blocked by activated vitamin D29
and vitamin D deficiency leads to abnormalities in contraction, proliferation, and collagen and renin gene expression in cardiomyocytes.30,31
It has recently been demonstrated that functional vitamin D receptor (VDR), as well as 1α-(OH)ase and 24-hydroxylase, are present in the ventricular myocardium, and that VDR expression is up-regulated with the induction of cardiac hypertrophy.32
VDR also has been shown to transcriptionally regulate both ANF and BNP expression by interacting with their promoters.32–34
In addition, VDR KO mice exhibit baseline cardiac hypertrophy and concomitant activation of the RAS35,36
and vitamin D therapy blocks the development of cardiac hypertrophy in the DSS rat model of cardiac hypertrophy.8
These findings suggest that the key components required for a functional vitamin D-dependent signalling system are present in the heart, and that vitamin D signalling may have an anti-hypertrophic and cardioprotective effects during the transition to heart failure. In this study, we further demonstrated that the anti-hypertrophic effect can also prevent progression of pre-existing cardiac hypertrophy as well as have a cardioprotective effect during the transition from compensated cardiac hypertrophy to decompensated heart failure. Further studies in other models of cardiac hypertrophy or heart failure, such as aortic banding or myocardial infarction models, would provide additional evidences to confirm if vitamin D supplementation has any cardiovascular beneficial effects. These studies are on going in our laboratory as well as others.
The relationship between vitamin D and PKC signalling is currently not well understood. The PKC family is divided into three subgroups: the classic (α, β1, β2, and γ), the novel (δ,
, η, and θ) and the atypical (ζ, ν, μ, and ι). Of particular interest are the classical PKCs, which are categorized on the basis of their Ca2+
-dependent activation. Specifically, PKCα expression has been shown to be up-regulated in animal models of heart failure,24
cardiac specific overexpression of PKCα leads to marked ventricular dysfunction and alterations in Ca2+
homeostasis, and the deletion of PKCα increases cardiac contractility.26
In this study, we found that PKCα activation, which may be involved in the progression to heart failure in this model, was effectively blocked by the PC treatment. These findings suggest that PKCα is an important signalling molecule that regulates cardiac function by sensing intracellular Ca2+
. This study is one of the first to demonstrate that vitamin D therapy attenuates PKCα activation in heart.
The effect of vitamin D has been shown to involve RAS activation.35
Li and co-authors found that VDR knockout (KO) mice exhibit increased cardiac renin gene expression and cardiac hypertrophy.35
They also found that kidney renin mRNA and protein levels were markedly increased in both VDR KO mice and 25-hydroxyvitamin D 1α-hydroxylase knockout mice36,37
suggesting that vitamin D signalling may be involved in renin production in the kidney and the heart. Inhibition of ACE by EP showed a significant benefit in progression to heart failure in our study. In comparison, our study also showed that there was an additive benefit of vitamin D therapy in the setting of ACE inhibition, which supports the existence of a RAS-independent effect of vitamin D. However, since we did not use a higher dose of ACE inhibitor, which would have had significant BP effect that could compound the interpretation, we cannot fully rule out the fact that higher dose of ACEI would fully account for the effect of PC. Further studies are needed to fully define the RAS-independent mechanism that may play a role in mediating the anti-hypertrophic and protective role of vitamin D therapy during the progression to heart failure.
Previous studies support the association of vitamin D deficiency with increased risk of developing heart failure. Thus, vitamin D deficiency may be an under-recognized, non-classic risk factor for CHF that is readily correctable. As trials are pursued in patients with cardiac hypertrophy with or at risk for heart failure (e.g. clinicaltrials.gov NCT00497146), there needs to be better understanding of the causal relationship between vitamin D status and cardiac dysfunction, and the mechanism of vitamin D's anti-hypertrophic and cardioprotective effects in heart failure needs to be examined. Nevertheless, vitamin D therapy promises to be potentially novel therapy that might complement currently available therapies for heart failure.