title: Hypertension is a conditional factor for the development of cardiac hypertrophy in type 2 diabetic mice.
abstract: BACKGROUND
  Type 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice.
  
  
  METHODS
  Thereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n = 9-10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation.
  
  
  RESULTS
  Vehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice.
  
  
  CONCLUSIONS
  Collectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling.
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Daniels
authors.affiliation: Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: Brouwers
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Wouter J A
authors.initials: WJ
authors.lastname: Derks
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Brouns
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Munts
authors.affiliation: Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Ger J
authors.initials: GJ
authors.lastname: van der Vusse
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Frans A
authors.initials: FA
authors.lastname: van Nieuwenhoven
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D048429:Cell Size; D003924:Diabetes Mellitus, Type 2 / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D004280:Dobutamine / Q000494:pharmacology; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D017127:Glycation End Products, Advanced; D000804:Angiotensin II; D004280:Dobutamine; D055372:AMP-Activated Protein Kinases