Effect of acute and chronic zofenopril administration on cardiac gene expression

Abstract

We investigated whether acute and chronic administration of zofenopril, an angiotensin converting enzyme inhibitor, may modulate the expression of genes which are involved in the pathophysiology of myocardial ischemia and heart failure. We used an acute and a chronic model. In the former isolated rat hearts were perfused for 120 min in the presence or in the absence of 10 μM zofenoprilat, the active metabolite of zofenopril. In the chronic model one group of rats was treated with zofenopril (15.2 mg/Kg die per os) for 15 days, while control rats were treated with the same diet, except that zofenopril was omitted. Total RNA was extracted from hearts, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression of α myosin heavy chain, superoxide dismutase, heat shock protein 70 (HSP70), nitric oxide synthase 2 and 3 (NOS2, NOS3), heme oxygenase 1, atrial natriuretic peptide (ANP), muscle phosphofructokinase. Acute or chronic zofenopril administration did not produce any change in hemodynamic variables. qRT-PCR experiments showed that in the acute model ANP expression was slightly although not significantly increased. In the chronic model, significant changes in gene expression were detected: in particular, HSP70 was upregulated (1.06 ± 0.38 vs. 0.72 ± 0.20 arbitrary units, P = 0.025), while NOS3 was downregulated (0.66 ± 0.06 vs. 0.83 ± 0.18 arbitrary units, P = 0.007). In the chronic model, liver samples were also assayed, but no significant change in the expression of any gene was detected. We conclude that zofenopril can produce heart-specific effects on gene expression. Persistent changes were detected with regard to specific heat shock protein and nitric oxide synthase subtypes. This action might contribute to the therapeutical response, and particularly to the increased resistance to ischemia.

Efficacy and Safety of Zofenopril Versus Ramipril in the Treatment of Myocardial Infarction and Heart Failure: A Review of the Published and Unpublished Data of the Randomized Double-Blind SMILE-4 Study

“…In Watanabe heritable hyperlipidemic rabbits, zofenopril reduced plasmatic low-density lipoprotein (LDL) oxidation, the number of macrophages-derived foam cells, and the wall-associated platelet deposition at the site of atherosclerotic lesions [ 9 ]. In rat models of ischemia and heart failure treated with zofenopril for 15 days (chronic model), zofenopril induced heat shock protein 70 expression and downregulated NO synthase 3, with a heart-specific effect on gene expression which partially explained an increased resistance to ischemia [ 10 ]. Zofenopril significantly augmented both plasma and myocardial H 2 S (sulfane sulfur) and NO levels in mice and plasma H 2 S in pigs, substances that could scavenge radical oxygen substrates and prevent myocardial damages associated with the ischemia/reperfusion injury [ 11 ].…”

Off-Target Effects of Angiotensin-Converting Enzyme Inhibitors: Additional Therapeutic Benefits

“…Другие наблюдения требуют более детального изучения, чтобы делать вывод об их терапевтическом значении. Однако авторы заключают, что среди плейотропного эффекта зофеноприла возможно влияние на экспрессию генов веществ, препятствующих ремоделированию миокарда [14].…”

Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management

“…The anti-malaria drugs quinacrine and emetine inhibited HSR in cancer cells by inducing hsp70 expression [ 89 ].…”