Na(+)-H(+) exchanger inhibitor prevents early death in hereditary cardiomyopathy.
Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular Na(+) and Ca(2+) overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented Na(+) and Ca(2+) overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent Na(+) and Ca(2+) overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy.
a Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada.
Ghassan
G
Bkaily
a Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada.
Mirna
M
Chahine
a Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada.
Johny
J
Al-Khoury
a Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada.
Levon
L
Avedanian
b Diabetes and Complication Research, Merck KGaA, D-64293 Darmstadt, Germany.
Norbert
N
Beier
b Diabetes and Complication Research, Merck KGaA, D-64293 Darmstadt, Germany.
Wolfgang
W
Scholz
a Department of Anatomy and Cell Biology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada.
Danielle
D
Jacques
D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D006224:Cricetinae; D003643:Death; D005260:Female; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use*
D006146:Guanidines; C481648:N-(2-methyl-4,5-bis(methylsulfonyl)benzoyl)guanidine; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1
ACE inhibitor; IECA; NHE-1; NHE-1 inhibitor EMD 87580; cardiomyopathie; cardiomyopathy; early death; heart failure; inhibiteur de la NHE-1 EMD 87580; insuffisance cardiaque; mort prématurée