Losartan treatment attenuates tumor-induced myocardial dysfunction

J Mol Cell Cardiol. 2015 Aug:85:37-47. doi: 10.1016/j.yjmcc.2015.05.007. Epub 2015 May 16.

Abstract

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction.

Methods and results: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8weeks of age. Simultaneously, mice were administered Losartan (10mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice.

Conclusions: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation.

Keywords: Calcium signaling; Cancer cachexia; Cardiomyocyte; Cardiovascular function; Losartan.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / complications*
  • Adenocarcinoma / pathology
  • Angiotensin II / blood
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Calcium Signaling
  • Cardiotonic Agents / pharmacology*
  • Cardiotonic Agents / therapeutic use
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control*
  • Cell Line, Tumor
  • Colonic Neoplasms / complications*
  • Colonic Neoplasms / pathology
  • Cytokines / blood
  • Drug Evaluation, Preclinical
  • Female
  • Glutathione / metabolism
  • Losartan / pharmacology*
  • Losartan / therapeutic use
  • Mice
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neoplasm Transplantation
  • Tumor Burden
  • Ventricular Remodeling / drug effects

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Cardiotonic Agents
  • Cytokines
  • Angiotensin II
  • Glutathione
  • Losartan