Deep ocean minerals inhibit IL-6 and IGFIIR hypertrophic signaling pathways to attenuate diabetes-induced hypertrophy in rat hearts

J Appl Physiol (1985). 2019 Aug 1;127(2):356-364. doi: 10.1152/japplphysiol.00184.2019. Epub 2019 May 16.


We previously reported that deep sea water (DSW) prolongs the life span of streptozotocin (STZ)-induced diabetic rats by the compensatory augmentation of the insulin like growth factor (IGF)-I survival signaling and inhibition of apoptosis. Here, we investigated the effects of DSW on cardiac hypertrophy in diabetic rats. Cardiac hypertrophy was induced in rats by using STZ (65 mg/kg) administered via IP injection. DSW was prepared by mixing DSW mineral extracts and desalinated water. Different dosages of DSW-1X (equivalent to 37 mg Mg2+·kg-1·day-1), 2X (equivalent to 74 mg Mg2+·kg-1·day-1) and 3X (equivalent to 111 mg Mg2+·kg-1·day-1) were administered to the rats through gavage for 4 wk. Cardiac hypertrophy was evaluated by the heart weight-to-body weight ratio and the cardiac tissue cross-sectional area after hematoxylin and eosin staining. The protein levels of the cardiac hypertrophy signaling molecules were determined by Western blot. Our results showed that the suppressive effects of the DSW treatment on STZ-induced cardiac hypertrophy were comparable to those of MgSO4 administration and that the hypertrophic marker brain natriuretic peptide (BNP) was decreased by DSW. In addition, DSW attenuated both the eccentric hypertrophy signaling pathway, IL-6-MEK-STAT3, and the concentric signaling pathway, IGF-II-PKCα-CaMKII, in DM rat hearts. The cardiac hypertrophy-associated activation of extracellular signal-regulated kinase (ERK) and the upregulation of the transcription factor GATA binding protein 4 (GATA4) were also negated by treatment with DSW. The results from this study suggest that DSW could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy.NEW & NOTEWORTHY Deep sea water, containing high levels of minerals, improve cardiac hypertrophy in diabetic rats through attenuating the eccentric signaling pathway, IL-6-MEK5-STAT3, and concentric signaling pathway, IGF2-PKCα-CaMKII. The results from this study suggest that deep sea water could be a potential therapeutic agent for the prevention and treatment of diabetic cardiac hypertrophy.

Keywords: IGFIIR; IL-6; cardiac hypertrophy; deep ocean minerals; diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cardiomegaly / metabolism*
  • Diabetes Mellitus, Experimental / metabolism*
  • Heart / physiopathology*
  • Interleukin-6 / metabolism*
  • MAP Kinase Signaling System / physiology
  • Male
  • Protein Kinase C-alpha / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, IGF Type 2 / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / physiology*


  • Il6 protein, rat
  • Interleukin-6
  • Receptor, IGF Type 2
  • STAT3 Transcription Factor
  • Protein Kinase C-alpha
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2