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Mitogen ‐ Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation – Induced Cardiac Hypertrophy

View Article: PubMed Central - PubMed

ABSTRACT

Background: The transient receptor potential vanilloid type 1 (TRPV1) is expressed in the cardiovascular system, and increased TRPV1 expression has been associated with cardiac hypertrophy. Nevertheless, the role of TRPV1 in the pathogenesis of cardiac hypertrophy and the underlying molecular mechanisms remain unclear.

Methods and results: In cultured cardiomyocytes, activation of TRPV1 increased cell size and elevated expression of atrial natriuretic peptide mRNA and intracellular calcium level, which was reversed by TRPV1 antagonist capsazepine. Increased expression of phosphorylated calmodulin‐dependent protein kinase IIδ and mitogen‐activated protein kinases were found in TRPV1 agonist capsaicin‐treated cardiomyocytes. Selective inhibitor of calmodulin‐dependent protein kinase IIδ decreased phosphorylation of extracellular signal–regulated kinases and p38. Capsaicin induced an increase in expression of ornithine decarboxylase protein, which is the key enzyme in polyamine biosynthesis in cardiomyocytes. Nevertheless, there was no obvious change of ornithine decarboxylase expression in TRPV1 knockdown cells after capsaicin treatment, and specific inhibitors of calmodulin‐dependent protein kinase IIδ or p38 downregulated the capsaicin‐induced expression of ornithine decarboxylase. Capsazepine alleviated the increase in cross‐sectional area of cardiomyocytes and the ratio of heart weight to body weight and improved cardiac function, including left ventricular internal end‐diastolic and ‐systolic dimensions and ejection fraction and fractional shortening percentages, in mice treated with transverse aorta constriction. Capsazepine also reduced expression of ornithine decarboxylase and cardiac polyamine levels. Transverse aorta constriction induced increases in phosphorylated calmodulin‐dependent protein kinase IIδ and extracellular signal–regulated kinases, and p38 and Serca2a were attenuated by capsazepine treatment.

Conclusions: This study revealed that the mitogen‐activated protein kinase signaling pathway and intracellular polyamines are essential for TRPV1 activation–induced cardiac hypertrophy.

No MeSH data available.


Related in: MedlinePlus

Antihypertrophy effect of TRPV1 antagonist in TAC‐treated mouse. A, Representative histological staining of cardiomyocytes in mice treated with vehicle control or CPZ (0.1, 0.5, or 2.5 mg/kg per day) at 8 weeks after TAC or sham surgery. Scale bar=25 μm. Analysis of cardiomyocyte cross‐sectional area (B) and ratio of heart weight normalized to body weight (C) was measured in the above groups (n=5 mice per group). *P<0.05, **P<0.01. D, Representative serial M‐model echocardiographic tracings in control, sham, vehicle, and CPZ (0.1, 0.5, or 2.5 mg/kg per day) treatment after TAC show LVIDs and LVIDd. CPZ indicates capsazepine; d, end‐diastole; D, diameter; HW/BW, heart weight/body weight ratio; LVAW, left ventricular anterior wall thickness; LVID, left ventricular internal dimension; LVPW, left ventricular posterior wall thickness; s, end‐systole; TAC, transverse aorta constriction.
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jah31675-fig-0005: Antihypertrophy effect of TRPV1 antagonist in TAC‐treated mouse. A, Representative histological staining of cardiomyocytes in mice treated with vehicle control or CPZ (0.1, 0.5, or 2.5 mg/kg per day) at 8 weeks after TAC or sham surgery. Scale bar=25 μm. Analysis of cardiomyocyte cross‐sectional area (B) and ratio of heart weight normalized to body weight (C) was measured in the above groups (n=5 mice per group). *P<0.05, **P<0.01. D, Representative serial M‐model echocardiographic tracings in control, sham, vehicle, and CPZ (0.1, 0.5, or 2.5 mg/kg per day) treatment after TAC show LVIDs and LVIDd. CPZ indicates capsazepine; d, end‐diastole; D, diameter; HW/BW, heart weight/body weight ratio; LVAW, left ventricular anterior wall thickness; LVID, left ventricular internal dimension; LVPW, left ventricular posterior wall thickness; s, end‐systole; TAC, transverse aorta constriction.

Mentions: Because the presented data showed that the TRPV1 antagonist CPZ alleviated CAP‐ or ANA‐induced cardiac hypertrophy in vitro, we next evaluated the effect of CPZ in TAC‐induced cardiac hypertrophy in vivo. Histological analysis showed that CPZ‐ or vehicle‐treated mice that underwent sham surgery showed no significant difference in cell size, whereas vehicle‐treated mice that underwent TAC had a significantly larger cross‐sectional area of cardiomyocytes compared with CPZ‐treated mice (0.5 and 2.5 mg/kg) that underwent TAC (Figure 5A and 5B). In addition, heart weight/body weight ratios in mice treated with 0.5 and 2.5 mg/kg CPZ and TAC were significantly lower compared with vehicle‐treated mice that underwent TAC (Figure 5C).


Mitogen ‐ Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation – Induced Cardiac Hypertrophy
Antihypertrophy effect of TRPV1 antagonist in TAC‐treated mouse. A, Representative histological staining of cardiomyocytes in mice treated with vehicle control or CPZ (0.1, 0.5, or 2.5 mg/kg per day) at 8 weeks after TAC or sham surgery. Scale bar=25 μm. Analysis of cardiomyocyte cross‐sectional area (B) and ratio of heart weight normalized to body weight (C) was measured in the above groups (n=5 mice per group). *P<0.05, **P<0.01. D, Representative serial M‐model echocardiographic tracings in control, sham, vehicle, and CPZ (0.1, 0.5, or 2.5 mg/kg per day) treatment after TAC show LVIDs and LVIDd. CPZ indicates capsazepine; d, end‐diastole; D, diameter; HW/BW, heart weight/body weight ratio; LVAW, left ventricular anterior wall thickness; LVID, left ventricular internal dimension; LVPW, left ventricular posterior wall thickness; s, end‐systole; TAC, transverse aorta constriction.
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Related In: Results  -  Collection

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jah31675-fig-0005: Antihypertrophy effect of TRPV1 antagonist in TAC‐treated mouse. A, Representative histological staining of cardiomyocytes in mice treated with vehicle control or CPZ (0.1, 0.5, or 2.5 mg/kg per day) at 8 weeks after TAC or sham surgery. Scale bar=25 μm. Analysis of cardiomyocyte cross‐sectional area (B) and ratio of heart weight normalized to body weight (C) was measured in the above groups (n=5 mice per group). *P<0.05, **P<0.01. D, Representative serial M‐model echocardiographic tracings in control, sham, vehicle, and CPZ (0.1, 0.5, or 2.5 mg/kg per day) treatment after TAC show LVIDs and LVIDd. CPZ indicates capsazepine; d, end‐diastole; D, diameter; HW/BW, heart weight/body weight ratio; LVAW, left ventricular anterior wall thickness; LVID, left ventricular internal dimension; LVPW, left ventricular posterior wall thickness; s, end‐systole; TAC, transverse aorta constriction.
Mentions: Because the presented data showed that the TRPV1 antagonist CPZ alleviated CAP‐ or ANA‐induced cardiac hypertrophy in vitro, we next evaluated the effect of CPZ in TAC‐induced cardiac hypertrophy in vivo. Histological analysis showed that CPZ‐ or vehicle‐treated mice that underwent sham surgery showed no significant difference in cell size, whereas vehicle‐treated mice that underwent TAC had a significantly larger cross‐sectional area of cardiomyocytes compared with CPZ‐treated mice (0.5 and 2.5 mg/kg) that underwent TAC (Figure 5A and 5B). In addition, heart weight/body weight ratios in mice treated with 0.5 and 2.5 mg/kg CPZ and TAC were significantly lower compared with vehicle‐treated mice that underwent TAC (Figure 5C).

View Article: PubMed Central - PubMed

ABSTRACT

Background: The transient receptor potential vanilloid type 1 (TRPV1) is expressed in the cardiovascular system, and increased TRPV1 expression has been associated with cardiac hypertrophy. Nevertheless, the role of TRPV1 in the pathogenesis of cardiac hypertrophy and the underlying molecular mechanisms remain unclear.

Methods and results: In cultured cardiomyocytes, activation of TRPV1 increased cell size and elevated expression of atrial natriuretic peptide mRNA and intracellular calcium level, which was reversed by TRPV1 antagonist capsazepine. Increased expression of phosphorylated calmodulin&#8208;dependent protein kinase II&delta; and mitogen&#8208;activated protein kinases were found in TRPV1 agonist capsaicin&#8208;treated cardiomyocytes. Selective inhibitor of calmodulin&#8208;dependent protein kinase II&delta; decreased phosphorylation of extracellular signal&ndash;regulated kinases and p38. Capsaicin induced an increase in expression of ornithine decarboxylase protein, which is the key enzyme in polyamine biosynthesis in cardiomyocytes. Nevertheless, there was no obvious change of ornithine decarboxylase expression in TRPV1 knockdown cells after capsaicin treatment, and specific inhibitors of calmodulin&#8208;dependent protein kinase II&delta; or p38 downregulated the capsaicin&#8208;induced expression of ornithine decarboxylase. Capsazepine alleviated the increase in cross&#8208;sectional area of cardiomyocytes and the ratio of heart weight to body weight and improved cardiac function, including left ventricular internal end&#8208;diastolic and &#8208;systolic dimensions and ejection fraction and fractional shortening percentages, in mice treated with transverse aorta constriction. Capsazepine also reduced expression of ornithine decarboxylase and cardiac polyamine levels. Transverse aorta constriction induced increases in phosphorylated calmodulin&#8208;dependent protein kinase II&delta; and extracellular signal&ndash;regulated kinases, and p38 and Serca2a were attenuated by capsazepine treatment.

Conclusions: This study revealed that the mitogen&#8208;activated protein kinase signaling pathway and intracellular polyamines are essential for TRPV1 activation&ndash;induced cardiac hypertrophy.

No MeSH data available.


Related in: MedlinePlus