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Abstract
We previously reported that Astragaloside IV (ASIV), a major active constituent of Astragalus membranaceus (Fisch) Bge protects against cardiac hypertrophy in rats induced by isoproterenol (Iso), however the mechanism underlying the protection remains unknown. Dysfunction of cardiac energy biosynthesis contributes to the hypertrophy and Nuclear Factor κB (NF-κB)/Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α (PGC-1α) signaling gets involved in the dysfunction. The present study was designed to investigate the mechanism by which ASIV improves the cardiac hypertrophy with focuses on the NF-κB/PGC-1α signaling mediated energy biosynthesis. Sprague-Dawley (SD) rats or Neonatal Rat Ventricular Myocytes (NRVMs) were treated with Iso alone or in combination with ASIV. The results showed that combination with ASIV significantly attenuated the pathological changes, reduced the ratios of heart weight/body weight and Left ventricular weight/body weight, improved the cardiac hemodynamics, down-regulated mRNA expression of Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP), increased the ratio of ATP/AMP, and decreased the content of Free Fat Acid (FFA) in heart tissue of rats compared with Iso alone. In addition, pretreatment with ASIV significantly decreased the surface area and protein content, down-regulated mRNA expression of ANP and BNP, increased the ratio of ATP/AMP, and decreased the content of FFA in NRVMs compared with Iso alone. Furthermore, ASIV increased the protein expression of ATP5D, subunit of ATP synthase and PGC-1α, inhibited translocation of p65, subunit of NF-κB into nuclear fraction in both rats and NRVMs compared with Iso alone. Parthenolide (Par), the specific inhibitor of p65, exerted similar effects as ASIV in NRVMs. Knockdown of p65 with siRNA decreased the surface areas and increased PGC-1α expression of NRVMs compared with Iso alone. The results suggested that ASIV protects against Iso-induced cardiac hypertrophy through regulating NF-κB/PGC-1α signaling mediated energy biosynthesis.
Highlights
Cardiac hypertrophy is a key compensatory mechanism in response to pressure or volume overload, involving some alterations in myocardial metabolism[1], inflammation[2], remodeling and neurohormonal activation
The results showed that rats treated with Iso alone demonstrated an increase in LVEDP and decreases in left ventricular systolic pressure (LVSP), +dP/ dtmax and-dP/dtmax compared with normal control rats
The results showed that treatment with Iso alone induced the cardiac hypertrophy represented by the thickness of the ventricular wall and the narrowness of the left ventricular cavity, increased the ratios of both HW/BW and LVW/BW and up-regulated the mRNA expression of Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) compared with normal control rats
Summary
Cardiac hypertrophy is a key compensatory mechanism in response to pressure or volume overload, involving some alterations in myocardial metabolism[1], inflammation[2], remodeling and neurohormonal activation. Sustained adrenergic receptor activation by Isoproterenol (Iso) is associated with cardiac hypertrophy[3]. Energy supply in the form of ATP is mandatory to sustain cardiac contractile and relaxation functions[6,7]. Both cardiac systolic and diastolic functions are dependent on mitochondrial-generated ATP, suggesting that mitochondrial bioenergetic decline contributes to the progression of hypertrophy[8]. ATP5D, subunit of ATP synthase is responsible for the ATP production and down-regulation of ATP5D is implied in the insufficient ATP production and cardiac hypertrophy
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