Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage. Herein, lipoproteins and liver enzymes from LGMD2B patients and dysferlin-null (Dysf) mice were analyzed. Simvastatin, which exhibits anti-muscle wasting effects in mouse models of DMD and corrects aberrant expression of key markers of lipid metabolism and endogenous cholesterol synthesis, was tested in Dysf mice. Muscle damage and fibrosis were assessed by immunohistochemistry and cholesterol signalling pathways via Western blot. LGMD2B patients show reduced serum high-density lipoprotein cholesterol (HDL-C) levels compared to healthy controls and exhibit a greater prevalence of abnormal total cholesterol (CHOL)/HDL-C ratios despite an absence of liver dysfunction. While Dysf mice presented with reduced CHOL and associated HDL-C and LDL-C-associated fractions, simvastatin treatment did not prevent muscle wasting in quadriceps and triceps muscle groups or correct aberrant low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) protein expression. LGMD2B patients present with reduced serum concentrations of HDL-C, a major metabolic comorbidity, and as a result, statin therapy is unlikely to prevent muscle wasting in this population. We propose that like DMD, LGMD2B should be considered as a new type of genetic dyslipidemia.
There are no therapeutics that directly enhance chronic endothelial nitric oxide (NO) release, which is typically associated with vascular homeostasis. In contrast, angiotensin II (AngII) receptor type 1 (AT1R) blockers (ARBs) can attenuate AngII-mediated oxidative stress, which often leads to increased endothelial NO bioavailability. Herein, we investigate the potential presence of direct, AngII/AT1R-independent ARB class effects on endothelial NO release and how this may result in enhanced aortic wall homeostasis and endothelial NO-specific transcriptome changes. Treatment of mice with four different ARBs induced sustained, long-term inhibition of vascular contractility by up to 82% at 16 weeks and 63% at 2 weeks, an effect reversed by L-NAME and absent in endothelial NO synthase (eNOS) KO mice or angiotensin converting enzyme inhibitor captopril-treated animals. In absence of AngII or in tissues with blunted AT1R expression or incubated with an AT2R blocker, telmisartan reduced vascular tone, supporting AngII/AT1R-independent pleiotropism. Finally, telmisartan was able to inhibit aging- and Marfan syndrome (MFS)-associated aortic root widening in NO-sensitive, BP-independent fashions, and correct aberrant TGF-β signaling. RNAseq analyses of aortic tissues identified early eNOS-specific transcriptome reprogramming of the aortic wall in response to telmisartan. This study suggests that ARBs are capable of major class effects on vasodilatory NO release in fashions that may not involve blockade of the AngII/AT1R pathway. Broader prophylactic use of ARBs along with identification of non-AngII/AT1R pathways activated by telmisartan should be investigated.
Introduction Sacubitril is a neprilysin inhibitor indicated for heart failure patients with reduced ejection fraction (HFReF), which causes protective natriuretic peptide accumulation. To maximize efficacy and minimize side effects, sacubitril is administered in combination with valsartan, a blood pressure‐lowering angiotensin II receptor blocker (ARB). We and others have shown that ARBs are capable of blood pressure lowering‐independent effects on vascular and lung remodeling, but whether the sacubitril/ARB combination shows greater anti‐vascular and lung remodeling effects is unknown. Objective Since ARBs are routinely prescribed to patients with Marfan syndrome, which is a fibrillin‐1 mutation‐induced connective tissue disease that causes aortic widening, dissection and lung emphysema, we sought to test the anti‐remodeling effects of low‐doses sacubitril/valsartan combination on the vascular and pulmonary complications associated with Marfan syndrome in mice. Results Treatment with low dose valsartan and sacubitril/valsartan (pure forms in drinking water) did not significantly lower blood pressure when compared with vehicle group in the C1039G fibrillin‐1 model of Marfan syndrome. There was a non‐significant inhibitory trend of Marfan‐associated aortic root widening with valsartan and especially sacubitril/valsartan, whereas only the latter induced a significant and near‐complete (74%) inhibition of Marfan‐associated ascending aorta widening (P<0.008). None of the treatment groups significantly reduced emphysema, loss of lung volume, change in hysteresis, tissue damping and resistance associated with Marfan syndrome. Conclusion Sacubitril/valsartan combination may be more clinically relevant than valsartan alone in settings of aortic dilation, even at low doses. Support or Funding Information Supported by Novartis Canada
Background and Purpose: Losartan is a well‐established anti‐hypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker (ARB) with unexpected therapeutic properties in a range of diseases not linked to hypertension, such as chronic lung diseases, Alzheimer's disease, muscular dystrophy and viral infections. This suggests that there is more to losartan than simple AngII‐ATR1 inhibition. We have recently shown that losartan can unexpectedly activate endothelial function in vivo via the endothelial release of protective nitric oxide (NO), which is typically associated with aerobic exercise and vascular homeostasis. Hence, losartan activation of endothelial NO release may be behind its protective non‐blood pressure‐related effects, although how this occurs is unknown. Losartan is a prodrug with many active metabolites that might be behind some of its unexpected therapeutic properties. Losartan first‐passage metabolism in the liver converts it to EXP3179 (losartan‐carboxaldehyde) believed to be devoid of ATR1 blocking effects followed by further metabolism into EXP3174 (losartan‐carboxylic acid), the main ATR1 blocker. Our goal is to determine whether first passage metabolism is required for losartan to activate endothelial NO release, or if bypassing liver metabolism via intraperitoneal (IP) injections of losartan metabolites EXP3179/3174 will result is similar biological activites, an indication that metabolites of losartan are not involved in this biological activity. Experimental Approach: C57B6/J mice were treated with 1) losartan potassium‐salt (LOS‐PS) for 2 weeks via drinking water (liver first passage‐dependent; 0.6 g/L) or 2) daily IP injections (first passage‐independent) of LOS‐PS, EXP3179 or EXP3174 (10 mg/kg). Systemic BP was noninvasively measured by a tail cuff system in mice anesthetized with isoflurane. NO‐dependent vasodilatory properties of losartan, EXP3179 and EXP3174 were evaluated in mouse aortic rings using dual‐wire myograph systems. Key Results: When losartan was delivered in drinking water, NO‐dependent vasorelaxation was increased by 57.6%. In stark contrast, IP injection of losartan resulted in unexpected increases in contractility by 124.9% compared to vehicle control, whereas IP EXP3179 and EXP3174 also increased vasoconstriction by 69.8% and 72.2% respectively. Vasodilatory effects of losartan were undetected in the presence of L‐NAME (NO synthase inhibitor), confirming that losartan exerts its effects in a NO‐dependent manner. Moreover, BP was decreased in all drug treated group of mice, confirming that all drugs were biologically active and blocking ATR1. Conclusion and implications: Our data unexpectedly show that losartan increases endothelial function in mice only when given in drinking water, which suggests that non‐EXP3179/74 metabolites may play an important role in endothelial NO activation. This also suggests that losartan‐induced BP lowering is separate from its endothelial NO activating properties.
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