Losartan treatment attenuates tumor-induced myocardial dysfunction

Abstract

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT)1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. Methods and Results: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8 weeks of age. Simultaneously, mice were administered Losartan (10 mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19 days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. Conclusions: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation.

Minocycline attenuates cardiac dysfunction in tumor-burdened mice

“…Our cardiomyocyte data agrees with previous findings, indicating no change in the sarcomere percent peak shortening in the c26 adenocarcinoma model of cancer cachexia [6, 22]. There were significant decreases in TPS90 and TR90 in tumor-bearing mice compared to control, as the velocity was unchanged.…”

“…Heart function is notably depressed in this cancer model with reduced FS% and EF [6, 20, 22, 27]. This reduction in the FS% and EF is the result of thinning of the posterior wall during systole, causing chamber expansion and reducing blood ejection.…”

“…Cardiomyocytes were isolated as previously described [22]. In brief, hearts were removed and digested using liberase and trypsin.…”

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…Furthermore, perindopril did not prevent the large decrease in cardiac ␣-myosin heavy chain mRNA expression in severely cachectic mice, which is typically associated with cardiac dysfunction (74). However, a recent study showed that the AT 1 antagonist losartan prevented the reductions in fractional shortening, ejection fraction, stroke volume, and posterior wall thickness and attenuated the increase in LV enddiastolic diameter during systole in C-26 tumor-bearing mice (102). Losartan treatment for 18 days also attenuated the decrease in systolic blood pressure and developed pressure and reduced tumor size in cachectic mice (102).…”

“…However, a recent study showed that the AT 1 antagonist losartan prevented the reductions in fractional shortening, ejection fraction, stroke volume, and posterior wall thickness and attenuated the increase in LV enddiastolic diameter during systole in C-26 tumor-bearing mice (102). Losartan treatment for 18 days also attenuated the decrease in systolic blood pressure and developed pressure and reduced tumor size in cachectic mice (102). The greater efficacy of AT 1 antagonism compared with ACE inhibition has important implications for the pathogenesis of cardiac cachexia in these preclinical models.…”