Telmisartan suppresses cardiac hypertrophy by inhibiting cardiomyocyte apoptosis via the NFAT/ANP/BNP signaling pathway

Abstract

Telmisartan, a type of angiotensin II (Ang II) receptor inhibitor, is a common agent used to treat hypertension in the clinic. Hypertension increases cardiac afterload and promotes cardiac hypertrophy. However, the ventricular Ang II receptor may be activated in the absence of hypertension. Therefore, telmisartan may reduce cardiac hypertrophy by indirectly ameliorating hypertensive symptoms and directly inhibiting the cardiac Ang II receptor. Nuclear factor of activated T-cells (NFAT) contributes to cardiac hypertrophy via nuclear translocation, which induces a cascade of atrial natriuretic peptide (ANP) and brain/B-type natriuretic peptide (BNP) expression and cardiomyocyte apoptosis. However, NFAT-mediated inhibition of cardiac hypertrophy by telmisartan remains poorly understood. The present study demonstrated that telmisartan suppressed cardiomyocyte hypertrophy in a mouse model of cardiac afterload and in cultured cardiomyocytes by inhibiting NFAT nuclear translocation, as well as by inhibiting ANP and BNP expression and cardiomyocyte apoptosis, in a dose-dependent manner. The present study provides a novel insight into the potential underlying mechanisms of telmisartan-induced inhibition of cardiomyocyte hypertrophy, which involves inhibition of NFAT activation, nuclear translocation and the ANP/BNP cascade.

Telmisartan cardioprotects from the ischaemic/hypoxic damage through a miR‐1‐dependent pathway

“…In order to investigate the effects of telmisartan treatment on hypoxic conditions alone, and not in combination with the serum and glucose deprivation (SGD), following the 6‐hour hypoxia the medium with CoCl 2 was replaced by DMEM without CoCl 2 for 2‐hour reoxygenation . Sixty minutes before the hypoxia/reoxygenation, cells were exposed to a dose of telmisartan (50 µmol/L; H/R Tel group) already reported as effective on H9c2 cells, and to its vehicle dimethyl sulfoxide (DMSO 1% in cell medium; H/R DMSO group) . At the end of the hypoxia/reoxygenation period, cell morphology was observed with optic microscopy (Leica DMi1, Germany).…”

“…26,27 Sixty minutes before the hypoxia/reoxygenation, 23 cells were exposed to a dose of telmisartan (50 µmol/L; H/R Tel group) already reported as effective on H9c2 cells, and to its vehicle dimethyl sulfoxide (DMSO 1% in cell medium; H/R DMSO group). 18 At the end of the hypoxia/reoxygenation period, cell morphology was observed with optic microscopy (Leica DMi1, Germany). According to previous experience, cells were seeded at 5 × 10 3 cells/cm 2 in 96-well plates for the viability assay; at 1 × 10 6 cells/cm 2 in 10 cm cell culture dishes for total RNA and protein detection; and at 1 × 10 4 cells/cm 2 in 24-well plates for immunofluorescence assay.…”

“…Telmisartan, an angiotensin II type 1 (AT1) receptor blocker and partial peroxisome proliferator‐activated receptor gamma (PPAR‐ γ ) agonist, has recently shown protective effects in the treatment of hypoxic/ischaemic cardiac damage related to increased levels of cardiac Cnx43 and reduced apoptosis . However, it has not yet been studied whether the effects of telmisartan on Cnx43 have been exerted through modifications of the expression of the cardiac miR‐1.…”

“…Telmisartan, an angiotensin II type 1 (AT1) receptor blocker and partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has recently shown protective effects in the treatment of hypoxic/ischaemic cardiac damage [15][16][17] related to increased levels of cardiac Cnx43 and reduced apoptosis. 18,19 However, it has not yet been studied whether the effects of telmisartan on Cnx43 have been exerted through modifications of the expression of the cardiac miR-1. Therefore, the first objective of the present study was to study the effects of telmisartan treatment on the cardiac expression of miR-1, Cnx43 and KCNQ1 in a rat model of myocardial ischaemia/reperfusion (I/R) injury.…”

Mitochondrial Transcription Factor A's role in heart failure.

“…De-phosphorylation of NFAT transcription factors by calcineurin allows for NFAT's transcriptional activation of nuclear encoded genes, influencing gene expression (Hogan et al 2003). The literature states that activation of the NFAT pathway directly stimulates pathological hypertrophic genes (Li et al 2017). Therefore, NFAT's inhibition may reduce pathological cardiac hypertrophy.…”