Paricalcitol reverses metabolic syndrome-associated heart failure
through enhanced mitochondrial fusion
Abstract
Background & Purpose: We have earlier shown that vitamin D deficiency
induces heart failure, in part, through insulin resistance. Whether
activation of vitamin D receptor can attenuate heart failure, associated
with metabolic syndrome, requires investigation. We aimed to assess
cardioprotective potential of paricalcitol, a vitamin D
receptor-activator, in high fat high fructose-fed rats. Experimental
approach: Male Sprague Dawley rats were fed with control (Con) or high
fat high fructose (HFHFrD) diet for 20 weeks. After 12 weeks, rats from
HFHFrD group were divided into: HFHFrD, HFHFrD+P (paricalcitol i.p. 0.08
ug/kg/day) and HFHFrD+E (enalapril maleate i.p. 10 mg/kg/day).
Intraperitoneal glucose tolerance test, blood pressure measurement and
2D echocardiography were performed. Cardiac fibrosis was assessed in
Masson trichrome-stained paraffin-embedded heart sections. Mitochondrial
DNA and proteins, and citrate synthase activity were measured in rat
hearts. VDR was silenced in H9c2 cardiomyoblasts and immunoblotting was
performed. Key Results: Paricalcitol improved glucose tolerance, serum
lipid profile and blood pressure in high fat high fructose-fed rats.
Paricalcitol reduced cardiac wall thickness, and increased ejection
fraction in high fat high fructose-fed rats, with no effect on
perivascular fibrosis. PGC1-α was uprgulated in HFHFrD+P group compared
to HFHFrD group, without significant difference in mitochondrial
content. Citrate synthase activity was significantly higher in HFHFrD+P
group compared to HFHFrD group. Rat hearts of HFHFrD+P group had
significantly higher expression of mitofusins. H9c2 cells with VDR
knockdown showed significantly lower expression of Mfn2. Conclusion &
Implications: Paricalcitol is cardioprotective in rats with metabolic
syndrome, through improved mitochondrial dynamics, indicating
repurposing potential.