Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats

Abstract

The incidence of left ventricular diastolic dysfunction (LVDD) increases in women following menopause, yet the mechanisms are unclear. Because mast cells participate in the pathological processes of various cardiac diseases, we hypothesized that mast cell inhibition would protect against estrogen loss-induced LVDD. The mast cell stabilizer, cromolyn sodium (30 mg/kg/day), or vehicle was administered subcutaneously by osmotic minipump to ovariectomized (OVX) female Fischer344×Brown Norway (F344BN) rats starting at four weeks after surgery. Eight weeks after OVX, systolic blood pressure increased by 20% in OVX vs. sham rats, and this effect was attenuated after four weeks of cromolyn treatment. Also, cromolyn mitigated the adverse reductions in myocardial relaxation (e′) and increases in left ventricle (LV) filling pressures (E/e′), LV mass, wall thicknesses, and interstitial fibrosis from OVX. While cardiac mast cell number was increased after OVX, cardiac chymase activity was not overtly altered by estrogen status and tended to decrease by cromolyn. Contrariwise, Ang II content was greater in hearts of OVX vs. sham rats, and cromolyn attenuated this effect. Taken together, mast cell inhibition with cromolyn attenuates LV remodeling and LVDD in OVX-F344BN rats possibly through actions on the heart level and/or via vasodilatory effects at the vascular level.

PKD knockdown inhibits pressure overload-induced cardiac hypertrophy by promoting autophagy via AKT/mTOR pathway

“…The end-diastolic interventricular septum thickness (IVSd), end-diastolic left ventricular (LV) posterior wall thickness (LVPWd), LV anterior wall thickness (LVAWd), LV end systolic diameter (LVSD), and end-systolic interventricular septum thickness (IVSs) were measured using M-mode. Ejection fraction (EF, %) and fractional shortening (FS, %) were calculated as described previously 17. Systolic blood pressure (SBP) was measured noninvasively using a volume-pressure recording tail-cuff method on conscious, restrained mice using the CODA 6 system (Kent Scientific Corp, Torrington, USA).…”

Mast cells participate in the development of diastolic dysfunction in diabetic obese mice

“…Importantly, circulating Tryptase was recently suggested to be a marker for cardiovascular diseases 23 . Moreover, mast cells have been previously involved in diastolic dysfunction induced by ovariectomy in rats 24 and diabetic cardiomyopathy in streptozotocin-treated mice 25 . The present study thus confirms the significant role of mast cells in cardiovascular diseases.…”

Female Heart Health: Is GPER the Missing Link?

“…In brief, 8 weeks of cromolyn sulfate administered subcutaneously to OVX-BNF344 rats attenuates the adverse effects of estrogen loss on diastolic function, interstitial collagen deposition, and collagen type 1A mRNA levels. Even though cardiac chymase activity in OVX rats is not overtly reduced by cromolyn (P < 0.06), cardiac Ang II content is reduced when compared with OVX vehicle, suggesting a role for mast cell derivedfactors and chymase/Ang II in the progression of cardiac aging and diastolic dysfunction after estrogen loss (154). Indeed, E 2 treatments favorably regulate cardiac mast cell number and prevent the adverse effects of OVX on cardiac remodeling and LV function in an Ang II-dependent rodent model of hypertension and LV diastolic dysfunction (150) and in models of surgically induced pressure overload (155) and volume overload (156,157).…”

“…OVX-related increases in chymase and Ang II expression were further associated with increases in cardiac fibrosis. Because mast cells are a major source of chymase (151,152) and generate Ang II from Ang I or Ang-(1-12) (153), we also determined the impact of mast cell inhibition by the mast stabilizer cromolyn sulfate on OVX-induced diastolic dysfunction (154). In brief, 8 weeks of cromolyn sulfate administered subcutaneously to OVX-BNF344 rats attenuates the adverse effects of estrogen loss on diastolic function, interstitial collagen deposition, and collagen type 1A mRNA levels.…”