Hypercholesterolemia downregulates autophagy in the rat heart

Abstract

BackgroundWe have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart.MethodsMale Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot.ResultsIsolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments.ConclusionsThis is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.

Simvastatin Improves the Jaw Bone Microstructural Defect Induced by High Cholesterol Diet in Rats by Regulating Autophagic Flux

“…Hypercholesterolemia can inhibit autophagy in the heart of rats [ 23 ]. Finally, we examined the effect of simvastatin on autophagic flux in the jaw bone tissues of HCD-fed rats by quantitative RT-PCR and immunohistochemistry.…”

Renin angiotensin system blockage by losartan neutralize hypercholesterolemia-induced inflammatory and oxidative injuries

“…Changing systolic and diastolic blood pressure as well as contractile-induced dysfunction in rodents that are fed on HCD [8] have been reported. Studies showed that cardiac phagocytosis could prevent hypercholesterolemia in rats [9]. Increased cholesterol intake was found to impair the renal function and to provoke kidney damage in rodents [10].…”

Baicalein neutralizes hypercholesterolemia-induced aggravation of oxidative injury in rats

“…Altered cardiac systolic and diastolic functions as well as contractile dysfunction were previously reported in rodents fed on HCD (3). In addition, basal cardiac autophagy was recently demonstrated to be suppresses by hypercholesterolemia in rats (4). Hypercholesterolemia was also reported in other studies to trigger lipids accumulation in liver, which negatively influence the hepatic functions (5,6).…”