Apelin Decreases Myocardial Injury and Improves Right Ventricular Function in Monocrotaline-Induced Pulmonary Hypertension

Am J Physiol Heart Circ Physiol. 2009 Jun;296(6):H2007-14. doi: 10.1152/ajpheart.00089.2009. Epub 2009 Apr 3.

Abstract

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 microg*kg(-1)*day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 +/- 38%), diameter of cardiomyocyte (40 +/- 10%), myocardial fibrosis (95 +/- 20%), peak systolic pressure (99 +/- 22%), peak rate of ventricular pressure rise (dP/dt(max); 74 +/- 24%), peak rate of ventricular pressure decline (dP/dt(min); 73 +/- 19%), and time constant tau (55 +/- 16%). In these animals, RV expression of apelin (-73 +/- 10%) and its receptor APJ (-61 +/- 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 +/- 713%), angiotensinogen (191 +/- 147%), endothelin-1 (RV, 497 +/- 156%; and LV, 799 +/- 309%), plasmatic levels of apelin (104 +/- 48%), and angiotensin 1-7 (161 +/- 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / blood
  • Angiotensin I / pharmacology
  • Animals
  • Antihypertensive Agents / blood
  • Antihypertensive Agents / pharmacology
  • Apelin
  • Apelin Receptors
  • Carrier Proteins / blood
  • Carrier Proteins / genetics*
  • Carrier Proteins / pharmacology
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism
  • Gene Expression Profiling
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / physiopathology*
  • Hypertrophy, Right Ventricular / chemically induced
  • Hypertrophy, Right Ventricular / metabolism
  • Hypertrophy, Right Ventricular / physiopathology
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Monocrotaline / toxicity
  • Myocardium / pathology
  • Peptide Fragments / blood
  • Peptide Fragments / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Ventricular Function, Right / physiology*

Substances

  • Antihypertensive Agents
  • Apelin
  • Apelin Receptors
  • Apln protein, rat
  • Aplnr protein, rat
  • Carrier Proteins
  • Endothelin-1
  • Intercellular Signaling Peptides and Proteins
  • Peptide Fragments
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Monocrotaline
  • Angiotensin I
  • angiotensin I (1-7)