Combination of tolvaptan and valsartan improves cardiac and renal functions in doxorubicin-induced heart failure in mice

Abstract

Heart failure (HF) is often complicated by renal dysfunction. Tolvaptan and valsartan are two well-known agents for the treatment of HF. However, the role of tolvaptan/valsartan combination on HF with renal dysfunction remains unclear. To establish a mice model with HF with renal dysfunction, mice were intraperitoneally injected with doxorubicin (Dox). Echocardiogram was applied to assess the left ventricular function. Additionally, serum aldosterone (ALD) and angiotensin II (Ang II) level in mice were determined by ELISA. Meanwhile, western blot assay was used to evaluate the expressions of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax) and cleaved caspase 3 in the heart and kidney tissues of mice. In this study, we found that compared to tolvaptan or valsartan alone treatment group, tolvaptan/valsartan combination obviously improved the left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS), and reduced serum ALD and Ang II level in Dox-treated mice. Additionally, tolvaptan/valsartan combination significantly prevented the inflammation and fibrosis of heart and kidney tissues in Dox-treated mice. Meanwhile, tolvaptan/valsartan combination notably inhibited the myocardial and renal cell apoptosis in Dox-treated mice via upregulation of Bcl-2 and downregulation of Bax and cleaved caspase 3, compared to the single drug treatment. Collectively, tolvaptan/valsartan combination could improve cardiac and renal functions, as well as prevent the fibrosis, inflammation and apoptosis of heart and kidney tissues in Dox-treated mice. Taken together, combining tolvaptan with valsartan might be a promising approach to achieve enhanced therapeutic effect for treatment of HF with renal dysfunction.

Role of mesenchymal stem cells‐derived exosomes on inflammation, apoptosis, fibrosis and telocyte modulation in doxorubicin‐induced cardiotoxicity: A closer look at the structural level

“…The Dox-induced cardiac fibrosis in the present study was displayed by Sirius red stain as a marker of collagen deposition and E-Cadherin immunoreaction as a marker of epithelialmesenchymal deposition. Comparable findings have also been recently displayed by Masson's assay, which revealed widespread collagen deposition with Dox cardiotoxicity (Yan et al, 2022).…”

Candesartan upregulates angiotensin‐converting enzyme 2 in kidneys of male animals by decreased ubiquitination

“…ARBs are used to improve proteinuria for adult patients with nephrotic syndrome 14 . The cardiac and renal functions are improved by the treatment in mice with doxorubicin‐induced heart failure 15 . For patients with diabetic nephropathy ranging from microalbuminuria to advanced renal failure, candesartan, a common ARB drug, significantly reduces urinary albumin excretion and has a protective effect on the kidneys 16 …”

“…14 The cardiac and renal functions are improved by the treatment in mice with doxorubicin-induced heart failure. 15 For patients with diabetic nephropathy ranging from microalbuminuria to advanced renal failure, candesartan, a common ARB drug, significantly reduces urinary albumin excretion and has a protective effect on the kidneys. 16 ACE2 is not only an important antihypertensive component of the RAS but also a major receptor for coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to enter host cells.…”